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Li X, Qu S. Novel insights into the central protective role of ACE2 in diabetic cardiomyopathy: from underlying signaling pathways to therapeutic perspectives. Mol Cell Biochem 2025:10.1007/s11010-024-05196-6. [PMID: 39928210 DOI: 10.1007/s11010-024-05196-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Accepted: 12/18/2024] [Indexed: 02/11/2025]
Abstract
Diabetic cardiomyopathy (DCM) is a cardiac complication specific to individuals with diabetes. It is defined as abnormalities of myocardial structure and function in diabetic patients who do not exhibit any obvious coronary artery disease, hypertensive heart disease, valvular heart disease, or inherited cardiomyopathy. A significant cardiovascular protective factor identified recently is angiotensin-converting enzyme 2 (ACE2), which is a rising star in the renin angiotensin system (RAS) and is responsible for the onset and progression of DCM. Nonetheless, there is not a comprehensive review outlining ACE2's effect on DCM. From the perspective of the pathogenesis of DCM, this review summarizes the myocardial protective role of ACE2 in the aspects of alleviating myocardial structure and dysfunction, correcting energy metabolism disorders, and restoring vascular function. Concurrently, we propose the connections between ACE2 and underlying signaling pathways, including ADAM17, Apelin/APJ, and Nrf2. Additionally, we highlight ACE2-related pharmaceutical treatment options and clinical application prospects for preventing and managing DCM. Further and underlying research is extensively required to completely comprehend the principal pathophysiological mechanism of DCM and the distinctive function of ACE2, switching experimental findings into clinical practice and identifying efficient therapeutic approaches.
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Affiliation(s)
- Xinyi Li
- Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Shunlin Qu
- Pathophysiology Department, Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, University of South China, Hongxiang Street, Hengyang, 421001, Hunan, China.
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2
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Zheng J, Hao H. Targeting renal damage: The ACE2/Ang-(1-7)/mas axis in chronic kidney disease. Cell Signal 2024; 124:111413. [PMID: 39293746 DOI: 10.1016/j.cellsig.2024.111413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 09/08/2024] [Accepted: 09/11/2024] [Indexed: 09/20/2024]
Abstract
The renin-angiotensin system (RAS) is a crucial factor in chronic kidney disease (CKD) progression, affecting renal function and contributing significantly to renal tissue inflammation and fibrosis. Activation of the classical ACE/Ang II/AT1 axis exacerbates renal damage, while the ACE2/Ang-(1-7)/Mas axis has shown promise in reducing CKD progression in numerous animal models. Recently, the ACE2/Ang-(1-7)/Mas axis has emerged as a promising target for CKD interventions. This review provides a comprehensive review of the pivotal role of this axis in CKD pathogenesis and systematically examines various molecules and pharmaceutical agents targeting this pathway. This review aims to elucidate potential strategies for delaying or halting CKD progression, offering patients more effective treatment options.
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Affiliation(s)
- Jian Zheng
- Department of Pathology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, PR China
| | - Hua Hao
- Department of Pathology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, PR China.
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3
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Tiwari P, Elgazzaz M, Lazartigues E, Hanif K. Effect of Diminazene Aceturate, an ACE2 activator, on platelet CD40L signaling induced glial activation in rat model of hypertension. Int Immunopharmacol 2024; 139:112654. [PMID: 38996777 DOI: 10.1016/j.intimp.2024.112654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 06/30/2024] [Accepted: 07/06/2024] [Indexed: 07/14/2024]
Abstract
Hypertension causes platelet activation and adhesion in the brain resulting in glial activation and neuroinflammation. Further, activation of Angiotensin-Converting Enzyme 2/Angiotensin (1-7)/Mas Receptor (ACE2/Ang (1-7)/MasR) axis of central Renin-Angiotensin System (RAS), is known to reduce glial activation and neuroinflammation, thereby exhibiting anti-hypertensive and anti-neuroinflammatory properties. Therefore, in the present study, the role of ACE2/Ang (1-7)/MasR axis was studied on platelet-induced glial activation and neuroinflammation using Diminazene Aceturate (DIZE), an ACE2 activator, in astrocytes and microglial cells as well as in rat model of hypertension. We found that the ACE2 activator DIZE, independently of its BP-lowering properties, efficiently prevented hypertension-induced glial activation, neuroinflammation, and platelet CD40-CD40L signaling via upregulation of ACE2/Ang (1-7)/MasR axis. Further, DIZE decreased platelet deposition in the brain by reducing the expression of adhesion molecules on the brain endothelium. Activation of ACE2 also reduced hypertension-induced endothelial dysfunction by increasing eNOS bioavailability. Interestingly, platelets isolated from hypertensive rats or activated with ADP had significantly increased sCD40L levels and induced significantly more glial activation than platelets from DIZE treated group. Therefore, injection of DIZE pre-treated ADP-activated platelets into normotensive rats strongly reduced glial activation compared to ADP-treated platelets. Moreover, CD40L-induced glial activation, CD40 expression, and NFкB-NLRP3 inflammatory signaling are reversed by DIZE. Furthermore, the beneficial effects of ACE2 activation, DIZE was found to be significantly blocked by MLN4760 (ACE2 inhibitor) as well as A779 (MasR antagonist) treatments. Hence, our study demonstrated that ACE2 activation reduced the platelet CD40-CD40L induced glial activation and neuroinflammation, hence imparted neuroprotection.
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Affiliation(s)
- Priya Tiwari
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Mona Elgazzaz
- Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Eric Lazartigues
- Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Kashif Hanif
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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4
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Wang Z, Fan H, Wu J. Food-Derived Up-Regulators and Activators of Angiotensin Converting Enzyme 2: A Review. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:12896-12914. [PMID: 38810024 PMCID: PMC11181331 DOI: 10.1021/acs.jafc.4c01594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 05/13/2024] [Accepted: 05/20/2024] [Indexed: 05/31/2024]
Abstract
Angiotensin-converting enzyme 2 (ACE2) is a key enzyme in the renin-angiotensin system (RAS), also serving as an amino acid transporter and a receptor for certain coronaviruses. Its primary role is to protect the cardiovascular system via the ACE2/Ang (1-7)/MasR cascade. Given the critical roles of ACE2 in regulating numerous physiological functions, molecules that can upregulate or activate ACE2 show vast therapeutic value. There are only a few ACE2 activators that have been reported, a wide range of molecules, including food-derived compounds, have been reported as ACE2 up-regulators. Effective doses of bioactive peptides range from 10 to 50 mg/kg body weight (BW)/day when orally administered for 1 to 7 weeks. Protein hydrolysates require higher doses at 1000 mg/kg BW/day for 20 days. Phytochemicals and vitamins are effective at doses typically ranging from 10 to 200 mg/kg BW/day for 3 days to 6 months, while Traditional Chinese Medicine requires doses of 1.25 to 12.96 g/kg BW/day for 4 to 8 weeks. ACE2 activation is linked to its hinge-bending region, while upregulation involves various signaling pathways, transcription factors, and epigenetic modulators. Future studies are expected to explore novel roles of ACE2 activators or up-regulators in disease treatments and translate the discovery to bedside applications.
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Affiliation(s)
- Zihan Wang
- Department
of Agricultural, Food and Nutritional Science, 4-10 Ag/For Building, University of Alberta, Edmonton, Alberta T6G 2P5, Canada
- Cardiovascular
Research Centre, University of Alberta, Edmonton, Alberta T6G 2R7, Canada
| | - Hongbing Fan
- Department
of Animal and Food Sciences, University
of Kentucky, Lexington, Kentucky 40546, United States
| | - Jianping Wu
- Department
of Agricultural, Food and Nutritional Science, 4-10 Ag/For Building, University of Alberta, Edmonton, Alberta T6G 2P5, Canada
- Cardiovascular
Research Centre, University of Alberta, Edmonton, Alberta T6G 2R7, Canada
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5
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Al Suleimani YM, Ali BH, Ali H, Manoj P, Almashaiki KS, Abdelrahman AM. The Salutary Effects of Diminazene, Lisinopril or Valsartan on Cisplatin - Induced Acute Kidney Injury in Rats: A Comparative Study. Physiol Res 2024; 73:227-237. [PMID: 38710058 PMCID: PMC11081186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 11/09/2023] [Indexed: 05/08/2024] Open
Abstract
Nephrotoxicity as a cause of acute kidney injury (AKI) induced by cisplatin (CP), limits its usefulness as an anticancer agent. Diminazene, an angiotensin converting enzyme 2 activator, exhibited renoprotective properties on rat models of kidney diseases. This research aims to investigate the salutary effect of diminazene in comparison with lisinopril or valsartan in CP-induced AKI. The first and second groups of rats received oral vehicle (distilled water) for 9 days, and saline injection or intraperitoneal CP (6 mg/kg) on day 6, respectively. Third, fourth, and fifth groups received intraperitoneal injections of CP on day 6 and diminazene (15 mg/kg/day, orally), lisinopril (10 mg/kg/day, orally), or valsartan (30 mg/kg/day, orally), for 9 days, respectively. 24h after the last day of treatment, blood and kidneys were removed under anesthesia for biochemical and histopathological examination. Urine during the last 24 h before sacrificing the rats was also collected. CP significantly increased plasma urea, creatinine, neutrophil gelatinase-associated lipocalin, calcium, phosphorus, and uric acid. It also increased urinary albumin/creatinine ratio, N-Acetyl-beta-D-Glucosaminidase/creatinine ratio, and reduced creatinine clearance, as well the plasma concentrations of inflammatory cytokines [plasma tumor necrosis factor-alpha, and interleukin-1beta], and significantly reduced antioxidant indices [catalase, glutathione reductase , and superoxide dismutase]. Histopathologically, CP treatment caused necrosis of renal tubules, tubular casts, shrunken glomeruli, and increased renal fibrosis. Diminazine, lisinopril, and valsartan ameliorated CP-induced biochemical and histopathological changes to a similar extent. The salutary effect of the three drugs used is, at least partially, due to their anti-inflammatory and antioxidant effects. Keywords: Cisplatin, Diminazene, ACE2 activator, Lisinopril, Valsartan, Acute kidney injury.
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Affiliation(s)
- Y M Al Suleimani
- Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, Al Khod, Oman,
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Dagar N, Habshi T, Shelke V, Jadhav HR, Gaikwad AB. Renoprotective effect of esculetin against ischemic acute kidney injury-diabetic comorbidity. Free Radic Res 2024; 58:69-87. [PMID: 38323807 DOI: 10.1080/10715762.2024.2313738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 01/11/2024] [Indexed: 02/08/2024]
Abstract
Mitophagy maintains cellular homeostasis by eliminating damaged mitochondria. Accumulated damaged mitochondria can lead to oxidative stress and cell death. Induction of the PINK1/Parkin-mediated mitophagy is reported to be renoprotective in acute kidney injury (AKI). Esculetin, a naturally available coumarin, has shown protective action against diabetic complications. However, its effect on AKI-diabetes comorbidity has not been explored yet. Therefore, we aimed to investigate the renoprotective effect of esculetin against AKI under diabetic conditions via regulating PINK1/Parkin-mediated mitophagy. For this, type 1 diabetic male Wistar rats were treated with two doses of esculetin (50 and 100 mg/kg/day orally) for five days followed by AKI induction by bilateral ischemic-reperfusion injury (IRI). NRK-52E cells grown in high glucose were exposed to sodium azide (10 mM) for induction of hypoxia/reperfusion injury (HRI) in-vitro. Esculetin (50 µM) treatment for 24 h was given to the cells before HRI. The in-vitro samples were utilized for cell viability and ΔΨm assay, immunoblotting, and immunofluorescence. Rats' plasma, urine, and kidney samples were collected for biochemical analysis, histopathology, and western blotting. Our results showed a significant decrease in kidney injury-specific markers and increased expression of mitophagy markers (PINK1 and Parkin) with esculetin treatment. Moreover, esculetin prevented the HRI and hyperglycemia-induced decrease in ΔΨm and autophagosome marker. Also, esculetin therapy reduced oxidative stress via increased Nrf2 and Keap1 expression. Esculetin attenuated AKI under diabetic condition by preventing mitochondrial dysfunction via inducing PINK1/Parkin-mediated mitophagy, suggesting its potential as an effective therapy for preventing AKI-diabetes comorbidity.
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Affiliation(s)
- Neha Dagar
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani, India
| | - Tahib Habshi
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani, India
| | - Vishwadeep Shelke
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani, India
| | - Hemant R Jadhav
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani, India
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Kale A, Shelke V, Habshi T, Dagar N, Gaikwad AB. ER stress modulated Klotho restoration: A prophylactic therapeutic strategy against acute kidney injury-diabetes comorbidity. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166905. [PMID: 37793463 DOI: 10.1016/j.bbadis.2023.166905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 09/10/2023] [Accepted: 09/27/2023] [Indexed: 10/06/2023]
Abstract
Klotho is a renoprotective factor that is at the forefront of research as a potential therapeutic agent and biomarker of acute kidney injury (AKI). Endoplasmic reticulum (ER) stress and Klotho downregulation are the critical hallmarks of AKI progression. Importantly, the crosstalk between ER and Klotho is still elusive in AKI under diabetic condition. Therefore, this study aimed to elucidate the affiliation between ER stress and Klotho regulation by using the ischemia-reperfusion renal injury (IRI) model based on male Wistar rats and the hypoxia-reperfusion injury (HRI) using NRK52E cells. Study outcomes demonstrated that the expression of AKI biomarkers: plasma creatinine, neutrophil gelatinase-associated lipocalin, kidney-injury molecule 1, and ER stress markers such as binding immunoglobulin binding protein (BiP), R/PKR-like ER kinase (PERK), and eukaryotic initiation factor-2 (eIF2α), were observed during AKI. Increased ER stress was associated with apoptosis induction as depicted by increased levels of Poly (ADP-ribose) polymerase (PARP) and caspase-7 and decreased tubular Klotho expression. Under diabetic settings, ER stress and apoptosis were exacerbated by additional Klotho downregulation. Treatment with Tauroursodeoxycholic acid (TUDCA) inhibited the ER stress, apoptosis, restored endogenous Klotho levels and ameliorated AKI under diabetic and non-diabetic conditions. ER stress and Klotho appear to be shared factors involved in the pathogenesis of AKI-diabetes comorbidity and targeting them could prove a novel therapeutic approach.
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Affiliation(s)
- Ajinath Kale
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan 333031, India
| | - Vishwadeep Shelke
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan 333031, India
| | - Tahib Habshi
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan 333031, India
| | - Neha Dagar
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan 333031, India
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan 333031, India.
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Almazmomi MA, Esmat A, Naeem A. Acute Kidney Injury: Definition, Management, and Promising Therapeutic Target. Cureus 2023; 15:e51228. [PMID: 38283512 PMCID: PMC10821757 DOI: 10.7759/cureus.51228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/28/2023] [Indexed: 01/30/2024] Open
Abstract
Acute kidney injury (AKI) is caused by a sudden loss of renal function, resulting in the build-up of waste products and a significant increase in mortality and morbidity. It is commonly diagnosed in critically ill patients, with its occurrence estimated at up to 50% in patients hospitalized in the intensive critical unit. Despite ongoing efforts, the death rate associated with AKI has remained high over the past half-century. Thus, it is critical to investigate novel therapy options for preventing the epidemic. Many studies have found that inflammation and Toll-like receptor-4 (TLR-4) activation have a significant role in the pathogenesis of AKI. Noteworthy, challenges in the search for efficient pharmacological therapy for AKI have arisen due to the multifaceted origin and complexity of the clinical history of people with the disease. This article focuses on kidney injury's epidemiology, risk factors, and pathophysiological processes. Specifically, it focuses on the role of TLRs especially type 4 in disease development.
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Affiliation(s)
- Meaad A Almazmomi
- Pharmaceutical Care Department, Ministry of National Guard - Health Affairs, Jeddah, SAU
- Pharmacology Department, Faculty of Medicine, King Abdulaziz University, Jeddah, SAU
| | - Ahmed Esmat
- Pharmacology Department, Faculty of Medicine, King Abdulaziz University, Jeddah, SAU
| | - Anjum Naeem
- Pharmaceutical Care Department, Ministry of National Guard - Health Affairs, Jeddah, SAU
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Suleimani YA, Maskari RA, Ali BH, Ali H, Manoj P, Al-Khamiyasi A, Abdelrahman AM. Nephroprotective effects of diminazene on doxorubicin-induced acute kidney injury in rats. Toxicol Rep 2023; 11:460-468. [PMID: 38053572 PMCID: PMC10693989 DOI: 10.1016/j.toxrep.2023.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 10/29/2023] [Accepted: 11/09/2023] [Indexed: 12/07/2023] Open
Abstract
This study aimed to investigate the potential protective effects of diminazene, an activator of angiotensin II converting enzyme (ACE2), on kidney function and structure in rats with acute kidney injury (AKI) induced by the anticancer drug doxorubicin (DOX). The impact of diminazene was compared to that of two other drugs: the ACE inhibitor lisinopril and the angiotensin II type 1 (AT1) receptor blocker valsartan. Rats were subjected to a single intraperitoneal injection of DOX (13.5 mg/kg) on the 5th day, either alone or in combination with diminazene (15 mg/kg/day), lisinopril (10 mg/kg/day), or valsartan (30 mg/kg/day) for 8 consecutive days. Various markers related to kidney function, oxidative stress, and inflammation were measured in plasma and urine. Additionally, kidney tissues were assessed histopathologically. DOX-induced nephrotoxicity was confirmed by elevated levels of plasma urea, creatinine, and neutrophil gelatinase-associated lipocalin (NGAL). DOX also led to increased urinary N-acetyl-β-D-glucosaminidase (NAG) activity and decreased creatinine clearance, albumin levels, and osmolality. Moreover, DOX caused a reduction in renal oxidative stress markers, including superoxide dismutase (SOD), glutathione reductase (GR), and catalase activities, while increasing malondialdehyde (MDA) levels. It also raised plasma inflammatory markers, tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β). Concurrently administering diminazene significantly mitigated these DOX-induced changes, including histopathological alterations like renal tubule necrosis, tubular casts, shrunken glomeruli, and increased renal fibrosis. Similar protective effects were observed with lisinopril and valsartan. These protective effects, at least in part, appear to result from the anti-inflammatory and antioxidant properties of these drugs. In summary, this study suggests that the administration of diminazene, lisinopril, or valsartan had comparable effects in ameliorating the biochemical and histopathological aspects of DOX-induced acute kidney injury in rats.
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Affiliation(s)
- Yousuf Al Suleimani
- Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, P.O. Box 35, Al Khod 123, Oman
| | - Raya Al Maskari
- Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, P.O. Box 35, Al Khod 123, Oman
| | - Badreldin H. Ali
- Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, P.O. Box 35, Al Khod 123, Oman
| | - Haytham Ali
- Department of Animal and Veterinary Sciences, College of Agricultural and Marine Sciences, Sultan Qaboos University, Muscat 123, Oman
| | - Priyadarsini Manoj
- Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, P.O. Box 35, Al Khod 123, Oman
| | - Ali Al-Khamiyasi
- Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, P.O. Box 35, Al Khod 123, Oman
| | - Aly M. Abdelrahman
- Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, P.O. Box 35, Al Khod 123, Oman
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Li F, Ma Z, Cai Y, Zhou J, Liu R. Optimizing diabetic kidney disease animal models: Insights from a meta-analytic approach. Animal Model Exp Med 2023; 6:433-451. [PMID: 37723622 PMCID: PMC10614131 DOI: 10.1002/ame2.12350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 08/12/2023] [Indexed: 09/20/2023] Open
Abstract
Diabetic kidney disease (DKD) is a prevalent complication of diabetes, often leading to end-stage renal disease. Animal models have been widely used to study the pathogenesis of DKD and evaluate potential therapies. However, current animal models often fail to fully capture the pathological characteristics of renal injury observed in clinical patients with DKD. Additionally, modeling DKD is often a time-consuming, costly, and labor-intensive process. The current review aims to summarize modeling strategies in the establishment of DKD animal models by utilizing meta-analysis related methods and to aid in the optimization of these models for future research. A total of 1215 articles were retrieved with the keywords of "diabetic kidney disease" and "animal experiment" in the past 10 years. Following screening, 84 articles were selected for inclusion in the meta-analysis. Review manager 5.4.1 was employed to analyze the changes in blood glucose, glycosylated hemoglobin, total cholesterol, triglyceride, serum creatinine, blood urea nitrogen, and urinary albumin excretion rate in each model. Renal lesions shown in different models that were not suitable to be included in the meta-analysis were also extensively discussed. The above analysis suggested that combining various stimuli or introducing additional renal injuries to current models would be a promising avenue to overcome existing challenges and limitations. In conclusion, our review article provides an in-depth analysis of the limitations in current DKD animal models and proposes strategies for improving the accuracy and reliability of these models that will inspire future research efforts in the DKD research field.
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Affiliation(s)
- Fanghong Li
- School of Chinese Materia MedicaBeijing University of Chinese MedicineBeijingChina
| | - Zhi Ma
- School of Life SciencesBeijing University of Chinese MedicineBeijingChina
| | - Yajie Cai
- School of Chinese Materia MedicaBeijing University of Chinese MedicineBeijingChina
| | - Jingwei Zhou
- Department of Nephrology, Dongzhimen HospitalThe First Affiliated Hospital of Beijing University of Chinese MedicineBeijingChina
| | - Runping Liu
- School of Chinese Materia MedicaBeijing University of Chinese MedicineBeijingChina
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Kim D, Jeong W, Kim Y, Lee J, Cho SW, Oh CM, Park R. Pharmacologic Activation of Angiotensin-Converting Enzyme II Alleviates Diabetic Cardiomyopathy in db/db Mice by Reducing Reactive Oxidative Stress. Diabetes Metab J 2023; 47:487-499. [PMID: 37096378 PMCID: PMC10404524 DOI: 10.4093/dmj.2022.0125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 06/29/2022] [Indexed: 04/26/2023] Open
Abstract
BACKGRUOUND Diabetes mellitus is one of the most common chronic diseases worldwide, and cardiovascular disease is the leading cause of morbidity and mortality in diabetic patients. Diabetic cardiomyopathy (DCM) is a phenomenon characterized by a deterioration in cardiac function and structure, independent of vascular complications. Among many possible causes, the renin-angiotensin-aldosterone system and angiotensin II have been proposed as major drivers of DCM development. In the current study, we aimed to investigate the effects of pharmacological activation of angiotensin-converting enzyme 2 (ACE2) on DCM. METHODS The ACE2 activator diminazene aceturate (DIZE) was administered intraperitoneally to male db/db mice (8 weeks old) for 8 weeks. Transthoracic echocardiography was used to assess cardiac mass and function in mice. Cardiac structure and fibrotic changes were examined using histology and immunohistochemistry. Gene and protein expression levels were examined using quantitative reverse transcription polymerase chain reaction and Western blotting, respectively. Additionally, RNA sequencing was performed to investigate the underlying mechanisms of the effects of DIZE and identify novel potential therapeutic targets for DCM. RESULTS Echocardiography revealed that in DCM, the administration of DIZE significantly improved cardiac function as well as reduced cardiac hypertrophy and fibrosis. Transcriptome analysis revealed that DIZE treatment suppresses oxidative stress and several pathways related to cardiac hypertrophy. CONCLUSION DIZE prevented the diabetes mellitus-mediated structural and functional deterioration of mouse hearts. Our findings suggest that the pharmacological activation of ACE2 could be a novel treatment strategy for DCM.
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Affiliation(s)
- Donghyun Kim
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Wooju Jeong
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Yumin Kim
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Jibeom Lee
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Sung Woo Cho
- Division of Cardiology, Department of Internal Medicine, Inje University Ilsan Paik Hospital, College of Medicine, Inje University, Goyang, Korea
- Cardiovascular and Metabolic Disease Center, Smart Marine Therapeutics Center, Inje University, Busan, Korea
| | - Chang-Myung Oh
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Raekil Park
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
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12
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Nemoto W, Yamagata R, Nakagawasai O, Tan-No K. Angiotensin-Related Peptides and Their Role in Pain Regulation. BIOLOGY 2023; 12:biology12050755. [PMID: 37237567 DOI: 10.3390/biology12050755] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/19/2023] [Accepted: 05/20/2023] [Indexed: 05/28/2023]
Abstract
Angiotensin (Ang)-generating system has been confirmed to play an important role in the regulation of fluid balance and blood pressure and is essential for the maintenance of biological functions. Ang-related peptides and their receptors are found throughout the body and exhibit diverse physiological effects. Accordingly, elucidating novel physiological roles of Ang-generating system has attracted considerable research attention worldwide. Ang-generating system consists of the classical Ang-converting enzyme (ACE)/Ang II/AT1 or AT2 receptor axis and the ACE2/Ang (1-7)/MAS1 receptor axis, which negatively regulates AT1 receptor-mediated responses. These Ang system components are expressed in various tissues and organs, forming a local Ang-generating system. Recent findings indicate that changes in the expression of Ang system components under pathological conditions are involved in the development of neuropathy, inflammation, and their associated pain. Here, we summarized the effects of changes in the Ang system on pain transmission in various organs and tissues involved in pain development process.
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Affiliation(s)
- Wataru Nemoto
- Division of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan
| | - Ryota Yamagata
- Division of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan
| | - Osamu Nakagawasai
- Division of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan
| | - Koichi Tan-No
- Division of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan
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13
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Zhang C, Cao X, Wang H, Li Z, Zhang Y. The ACE2 activator diminazene aceturate ameliorates colitis by repairing the gut-vascular barrier in mice. Microvasc Res 2023; 148:104544. [PMID: 37127063 DOI: 10.1016/j.mvr.2023.104544] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 02/21/2023] [Accepted: 04/25/2023] [Indexed: 05/03/2023]
Abstract
Alleviating vascular barrier injury improves colitis. Angiotensin converting enzyme 2/angiotensin 1-7/Mas receptor (ACE2/Ang1-7/MasR) axis-related drugs have various biological properties, such as inhibition of inflammation and fibrosis, but their role in improving the gut-vascular barrier (GVB) has rarely been reported. This study aims to investigate the effects of diminazene aceturate (DIZE), an ACE2 activator, on vascular barrier damage in colitis. Mice were randomly divided into three groups: control, dextran sulfate sodium salt (DSS), and DIZE+DSS. Mice in the DSS group drank DSS for 8 days starting on day 4. Mice in the DIZE+DSS group were pregavaged with DIZE for 3 days and then drank DSS for 8 days while continuing to be gavaged with DIZE for 4 days. Mice were euthanized and samples were collected on the last day. Injury to colonic structure and colonic microvasculature was assessed by visual observation and appropriate staining. DSS-induced colonic and microvascular pathological damage in mice was substantially reversed by DIZE treatment. Molecular pathways were investigated by Western blot, quantitative real-time polymerase chain reaction (qRT-PCR), and enzyme linked immunosorbent assay (ELISA). DSS treatment upregulated angiotensin converting enzyme (ACE), angiotensin type 1 receptor (AT1R) protein, pro-inflammatory cytokines and inhibited tight junction-related protein expression. DIZE treatment activated ACE2/MasR protein expression and reversed epithelial barrier damage and inflammatory infiltration during DSS injury. In addition, DIZE treatment inhibited vascular endothelial growth factor A/vascular endothelial growth factor receptor 2/proto-oncogene tyrosine-protein kinase Src (VEGFA/VEGFR2/Src) pathway activation and restored vascular adhesion-linker protein vascular endothelial cadherin (VE-cadherin) expression during DSS injury. In conclusion, DIZE treatment ameliorated colitis, which was associated with balancing the two axes of the renin-angiotensin system (RAS) and repairing the GVB injury.
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Affiliation(s)
- Chonghao Zhang
- Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Xiyue Cao
- Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Huanhuan Wang
- Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Zhiqiang Li
- Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Yuanshu Zhang
- Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
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14
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Hulme J. COVID-19 and Diarylamidines: The Parasitic Connection. Int J Mol Sci 2023; 24:6583. [PMID: 37047556 PMCID: PMC10094973 DOI: 10.3390/ijms24076583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 03/28/2023] [Accepted: 03/30/2023] [Indexed: 04/05/2023] Open
Abstract
As emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants (Omicron) continue to outpace and negate combinatorial vaccines and monoclonal antibody therapies targeting the spike protein (S) receptor binding domain (RBD), the appetite for developing similar COVID-19 treatments has significantly diminished, with the attention of the scientific community switching to long COVID treatments. However, treatments that reduce the risk of "post-COVID-19 syndrome" and associated sequelae remain in their infancy, particularly as no established criteria for diagnosis currently exist. Thus, alternative therapies that reduce infection and prevent the broad range of symptoms associated with 'post-COVID-19 syndrome' require investigation. This review begins with an overview of the parasitic-diarylamidine connection, followed by the renin-angiotensin system (RAS) and associated angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSSR2) involved in SARS-CoV-2 infection. Subsequently, the ability of diarylamidines to inhibit S-protein binding and various membrane serine proteases associated with SARS-CoV-2 and parasitic infections are discussed. Finally, the roles of diarylamidines (primarily DIZE) in vaccine efficacy, epigenetics, and the potential amelioration of long COVID sequelae are highlighted.
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Affiliation(s)
- John Hulme
- Department of Bionano Technology, Gachon Bionano Research Institute, Gachon University, 1342 Sungnam-daero, Sujung-gu, Seongnam-si 461-701, Republic of Korea
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15
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Abdelrahman AM, Ali BH, Ali H, Manoj P, Al-Suleimani Y. The effect of diminazene, an angiotensin-converting enzyme 2 activator, on adenine-induced chronic kidney disease in rats. Fundam Clin Pharmacol 2023; 37:235-244. [PMID: 36300543 DOI: 10.1111/fcp.12845] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 09/15/2022] [Accepted: 10/20/2022] [Indexed: 11/09/2022]
Abstract
The present study investigated the effect of diminazene, lisinopril, or valsartan on adenine-induced chronic kidney disease (CKD) in rats. The animals were divided into five groups (n = 6). The first and second groups received normal diet and adenine in the feed at a dose of 0.25% w/w for 35 days, respectively. The third, fourth, and fifth groups were treated as the second group but also received diminazene (15 mg/kg/day), lisinopril (10 mg/kg/day), and valsartan (30 mg/kg/day), respectively, for 35 days. Adenine significantly increased plasma urea, creatinine, neutrophil gelatinase-associated lipocalin (NGAL), calcium, phosphorus, and uric acid. In addition, adenine increased urinary albumin/creatinine ratio and N-Acetyl-β-D-glucosaminidase (NAG)/creatinine ratio and reduced creatinine clearance. Adenine also significantly increased the plasma concentrations of inflammatory cytokines (plasma tumor necrosis factor-alpha [TNF-α] and interleukin-1beta [IL-1β]) and significantly reduced antioxidant indices (catalase, glutathione reductase [GR], and superoxide dismutase [SOD]). Histopathologically, renal tissue from adenine-treated rats showed necrosis of renal tubules, tubular casts, shrunken glomeruli, and increased renal fibrosis. All drugs ameliorated adenine-induced biochemical and histopathological changes. The protective effect of the three drugs used is, at least partially, due to their anti-inflammatory and antioxidant effects. Our results show that administration of diminazene, lisinopril, or valsartan had a comparable effect on the reversal of the biochemical and histopathological indices of adenine-induced CKD in rats.
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Affiliation(s)
- Aly M Abdelrahman
- Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, Al Khod, Oman
| | - Badreldin H Ali
- Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, Al Khod, Oman
| | - Haytham Ali
- Department of Animal and Veterinary Sciences, College of Agricultural and Marine Sciences, Sultan Qaboos University, Muscat, Oman
| | - Priyadarsini Manoj
- Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, Al Khod, Oman
| | - Yousuf Al-Suleimani
- Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, Al Khod, Oman
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16
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Kim Y, Kim J, Han SJ. Diminazene aceturate exacerbates renal fibrosis after unilateral ureteral obstruction in female mice. Kidney Res Clin Pract 2023; 42:188-201. [PMID: 37037481 PMCID: PMC10085718 DOI: 10.23876/j.krcp.22.033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 06/07/2022] [Indexed: 04/03/2023] Open
Abstract
Background: Diminazene aceturate (DIZE), an angiotensin-converting enzyme 2 (ACE2) activator, exerts anti-inflammatory and antifibrotic effects in a variety of human chronic diseases. However, the role of DIZE in kidney fibrosis and the underlying mechanism remain unclear. Therefore, we investigated the effects of DIZE on the progression of renal fibrosis after unilateral ureteral obstruction (UUO), a well-established model of chronic kidney disease. Methods: C57BL/6 female or male mice were subjected to right UUO. Mice received 15 mg/kg DIZE or vehicle (saline) daily. On the 7th day after UUO, kidneys were collected for analysis of renal fibrosis (α-smooth muscle actin, phosphorylated SMAD3, transforming growth factor (TGF)-β, Masson’s trichrome, and Sirius red staining), inflammation (macrophage infiltration, proinflammatory cytokines/chemokines), apoptosis/necrotic cell death (TUNEL and periodic acid-Schiff staining), and ACE2 activity and messenger RNA (mRNA) expression.Results: Treatment with DIZE exacerbated renal fibrosis by upregulating the profibrotic TGF-β/SMAD3 pathway, proinflammatory cytokine/chemokines (interleukin [IL]-1β, monocyte chemoattractant protein-1, IL-6, and macrophage inflammatory protein-2) levels, M2 macrophage accumulation (CD206, IL-4, IL-10, and CX3CL1), and apoptotic/necrotic cell death in the obstructed kidneys of female mice but not male mice. However, DIZE treatment had no effect on ACE2 activity or mRNA expression.Conclusion: DIZE exacerbates UUO-induced renal fibrosis by aggravating tubular damage, apoptosis, and inflammation through independent of Ang (1–7), Ang 2 levels, and ACE2 expression/activity, rather than protecting against renal fibrosis after UUO. DIZE also has powerful effects on recruiting macrophages, including the M2-polarized subtype, in female UUO mice.
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Affiliation(s)
- Yosep Kim
- Department of Biotechnology, College of Fisheries Sciences, Pukyong National University, Busan, Republic of Korea
| | - Jongwan Kim
- Department of Medical Laboratory Science, Dong-Eui Institute of Technology, Busan, Republic of Korea
- Jongwan Kim Department of Medical Laboratory Science, Dong-Eui Institute of Technology, 54 Yangji-ro, Busanjin-gu, Busan 47230, Republic of Korea. E-mail:
| | - Sang Jun Han
- Department of Biotechnology, College of Fisheries Sciences, Pukyong National University, Busan, Republic of Korea
- Correspondence: Sang Jun Han Department of Biotechnology, College of Fisheries Sciences, Pukyong National University, 45 Yongso-ro, Nam-gu, Busan 48513, Republic of Korea. E-mail:
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17
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Evaluating the potential of tauroursodeoxycholic acid as add-on therapy in amelioration of streptozotocin-induced diabetic kidney disease. Eur J Pharmacol 2023; 942:175528. [PMID: 36690052 DOI: 10.1016/j.ejphar.2023.175528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 01/18/2023] [Accepted: 01/19/2023] [Indexed: 01/22/2023]
Abstract
The bile acid tauroursodeoxycholic acid (TUDCA) is of natural origin and is used in traditional Chinese medicine for centuries. Earlier its use was limited to biliary disorders but owing to its pleiotropic effects dietary TUDCA supplementation is under clinical trials for diseases including type 1 and 2 diabetic complications. The current study aims to evaluate the potential and underlying molecular mechanism of the TUDCA as a monotherapy and as an add-on therapy to telmisartan, an angiotensin II type 1 receptor (AT1R) blocker against diabetic kidney disease (DKD). We employed both in-vitro and in-vivo approaches where NRK-52E cells were incubated with high glucose, and DKD was induced in Wistar rats using streptozotocin (55 mg/kg, i.p.). After 4 weeks, animals were administered with TUDCA (250 mg/kg, i.p.), telmisartan (10 mg/kg, p.o.), and their combination for 4 weeks. Plasma was collected for the biochemical estimation and kidneys were used for immunoblotting, PCR, and histopathological analysis. Similarly, for in-vitro experiments, cells were exposed to 1000 μM of TUDCA and 10 μM of telmisartan, and their combination, followed by cell lysate collection and immunoblotting analysis. We observed that the addition of TUDCA to conventional telmisartan treatment was more effective in restoring the renal function decline and suppressing the apoptotic and fibrotic signaling as compared to monotherapies of AT1R blocker and ER stress inhibitor. The results implicate the utility of traditionally used TUDCA as a potential renoprotective compound. Since, both TUDCA and telmisartan are approved for clinical usage, thus concomitant administration of them could be a novel therapeutic strategy against DKD.
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18
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Tiwari V, Singh J, Tiwari P, Chaturvedi S, Gupta S, Mishra A, Singh S, Wahajuddin M, Hanif K, Shukla S. ACE2/ANG-(1-7)/Mas receptor axis activation prevents inflammation and improves cognitive functions in streptozotocin induced rat model of Alzheimer's disease-like phenotypes. Eur J Pharmacol 2023; 946:175623. [PMID: 36871666 DOI: 10.1016/j.ejphar.2023.175623] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 01/25/2023] [Accepted: 02/23/2023] [Indexed: 03/06/2023]
Abstract
Activation of the renin-angiotensin system (RAS), by Angiotensin converting enzyme/Angiotensin II/Angiotensin receptor-1 (ACE/Ang II/AT1 R) axis elicits amyloid deposition and cognitive impairment. Furthermore, ACE2 induced release of Ang-(1-7) binds with the Mas receptor and autoinhibits ACE/Ang II/AT1 axis activation. Inhibition of ACE by perindopril has been reported to improve memory in preclinical settings. However, the functional significance and mechanism by which ACE2/Mas receptor regulate cognitive functions and amyloid pathology is not known. The present study is aimed to determine the role of ACE2/Ang-(1-7)/Mas receptor axis in STZ induced rat model of Alzheimer's disease (AD). We have used pharmacological, biochemical and behavioural approaches to identify the role of ACE2/Ang-(1-7)/Mas receptor axis activation on AD-like pathology in both in vitro and invivo models. STZ treatment enhances ROS formation, inflammation markers and NFκB/p65 levels which are associated with reduced ACE2/Mas receptor levels, acetylcholine activity and mitochondrial membrane potential in N2A cells. DIZE mediated ACE2/Ang-(1-7)/Mas receptor axis activation resulted in reduced ROS generation, astrogliosis, NFκB level and inflammatory molecules and improved mitochondrial functions along with Ca2+ influx in STZ treated N2A cells. Interestingly, DIZE induced activation of ACE2/Mas receptor significantly restored acetylcholine levels and reduced amyloid-beta and phospho-tau deposition in cortex and hippocampus that resulted in improved cognitive function in STZ induced rat model of AD-like phenotypes. Our data indicate that ACE2/Mas receptor activation is sufficient to prevented cognitive impairment and progression of amyloid pathology in STZ induced rat model of AD-like phenotypes. These findings suggest the potential role of ACE2/Ang-(1-7)/Mas axis in AD pathophysiology by regulating inflammation cognitive functions.
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Affiliation(s)
- Virendra Tiwari
- Division of Neuroscience and Ageing Biology, CSIR- Central Drug Research Institute, Lucknow, 226031, (U.P), India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Jitendra Singh
- Division of Neuroscience and Ageing Biology, CSIR- Central Drug Research Institute, Lucknow, 226031, (U.P), India
| | - Priya Tiwari
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India; Division of Pharmacology, CSIR- Central Drug Research Institute, Lucknow, 226031, (U.P), India
| | - Swati Chaturvedi
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India; Division of Pharmaceutics and Pharmacokinetics, CSIR - Central Drug Research Institute, Lucknow, 226031, (U.P), India
| | - Shivangi Gupta
- Division of Neuroscience and Ageing Biology, CSIR- Central Drug Research Institute, Lucknow, 226031, (U.P), India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Akanksha Mishra
- Division of Neuroscience and Ageing Biology, CSIR- Central Drug Research Institute, Lucknow, 226031, (U.P), India; Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, 01595, USA
| | - Sonu Singh
- Division of Neuroscience and Ageing Biology, CSIR- Central Drug Research Institute, Lucknow, 226031, (U.P), India; Department of Neuroscience, School of Medicine, University of Connecticut (Uconn) Health Center, 263 Farmington Avenue, L-4078, Farmington, CT, 06030, USA
| | - Muhammad Wahajuddin
- Division of Pharmaceutics and Pharmacokinetics, CSIR - Central Drug Research Institute, Lucknow, 226031, (U.P), India; Institute of Cancer Therapeutics, University of Bradford, Bradford, BD7 1DP, United Kingdom
| | - Kashif Hanif
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India; Division of Pharmacology, CSIR- Central Drug Research Institute, Lucknow, 226031, (U.P), India
| | - Shubha Shukla
- Division of Neuroscience and Ageing Biology, CSIR- Central Drug Research Institute, Lucknow, 226031, (U.P), India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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19
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Devaux CA, Camoin-Jau L. An update on angiotensin-converting enzyme 2 structure/functions, polymorphism, and duplicitous nature in the pathophysiology of coronavirus disease 2019: Implications for vascular and coagulation disease associated with severe acute respiratory syndrome coronavirus infection. Front Microbiol 2022; 13:1042200. [PMID: 36519165 PMCID: PMC9742611 DOI: 10.3389/fmicb.2022.1042200] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 11/07/2022] [Indexed: 08/01/2023] Open
Abstract
It has been known for many years that the angiotensin-converting enzyme 2 (ACE2) is a cell surface enzyme involved in the regulation of blood pressure. More recently, it was proven that the severe acute respiratory syndrome coronavirus (SARS-CoV-2) interacts with ACE2 to enter susceptible human cells. This functional duality of ACE2 tends to explain why this molecule plays such an important role in the clinical manifestations of coronavirus disease 2019 (COVID-19). At the very start of the pandemic, a publication from our Institute (entitled "ACE2 receptor polymorphism: susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome"), was one of the first reviews linking COVID-19 to the duplicitous nature of ACE2. However, even given that COVID-19 pathophysiology may be driven by an imbalance in the renin-angiotensin system (RAS), we were still far from understanding the complexity of the mechanisms which are controlled by ACE2 in different cell types. To gain insight into the physiopathology of SARS-CoV-2 infection, it is essential to consider the polymorphism and expression levels of the ACE2 gene (including its alternative isoforms). Over the past 2 years, an impressive amount of new results have come to shed light on the role of ACE2 in the pathophysiology of COVID-19, requiring us to update our analysis. Genetic linkage studies have been reported that highlight a relationship between ACE2 genetic variants and the risk of developing hypertension. Currently, many research efforts are being undertaken to understand the links between ACE2 polymorphism and the severity of COVID-19. In this review, we update the state of knowledge on the polymorphism of ACE2 and its consequences on the susceptibility of individuals to SARS-CoV-2. We also discuss the link between the increase of angiotensin II levels among SARS-CoV-2-infected patients and the development of a cytokine storm associated microvascular injury and obstructive thrombo-inflammatory syndrome, which represent the primary causes of severe forms of COVID-19 and lethality. Finally, we summarize the therapeutic strategies aimed at preventing the severe forms of COVID-19 that target ACE2. Changing paradigms may help improve patients' therapy.
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Affiliation(s)
- Christian A. Devaux
- Aix-Marseille Université, IRD, APHM, MEPHI, IHU–Méditerranée Infection, Marseille, France
- Center National de la Recherche Scientifique, Marseille, France
| | - Laurence Camoin-Jau
- Aix-Marseille Université, IRD, APHM, MEPHI, IHU–Méditerranée Infection, Marseille, France
- Laboratoire d’Hématologie, Hôpital de La Timone, APHM, Boulevard Jean-Moulin, Marseille, France
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20
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Esfahani SH, Jayaraman S, Karamyan VT. Is Diminazene an Angiotensin-Converting Enzyme 2 (ACE2) Activator? Experimental Evidence and Implications. J Pharmacol Exp Ther 2022; 383:149-156. [PMID: 36507848 PMCID: PMC9553104 DOI: 10.1124/jpet.122.001339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 08/17/2022] [Indexed: 01/07/2023] Open
Abstract
Antiprotozoal veterinary drug diminazene aceturate (DIZE) has been proposed to be an angiotensin-converting enzyme 2 (ACE2) activator. Since then, DIZE was used in dozens of experimental studies, but its mechanism of action attributed to ACE2 activation and enhanced formation of angiontensin-(1-7) [Ang-(1-7)] from Ang II was not carefully verified. The aim of this study was to confirm the effect of DIZE on catalytic activity of ACE2 and extend it to other peptidases involved in formation and degradation of Ang-(1-7). Concentration-dependent effect of DIZE on the initial rate of a fluorogenic substrate hydrolysis by human and mouse recombinant ACE2 was measured at assay conditions imitating that of the original report, but no activation of ACE2 was documented. Similar results were obtained with a more physiologically relevant assay buffer. In addition, DIZE did not affect activity of recombinant neprilysin, neurolysin, thimet oligopeptidase, and ACE. Efficiency of the fluorogenic substrate hydrolysis (Vmax/Km value) by ACE2 in response to different concentrations of DIZE was also measured, but no substantial effects were documented. Likewise, DIZE failed to enhance the hydrolysis of ACE2 endogenous substrate Ang II. Identity of the commercial recombinant ACE2 variants used in these experiments was confirmed by inhibition with two well characterized inhibitors (DX600 and MLN4760), activation by NaCl, and Western Blotting using validated antibodies. These observations challenge the widely accepted notion about the molecular mechanism of DIZE action and call for not ascribing this molecule as an ACE2 activator. SIGNIFICANCE STATEMENT: DIZE has been proposed and widely used in experimental studies as an ACE2 activator. The detailed in vitro pharmacological studies failed to confirm that DIZE is an ACE2 activator. In addition, DIZE did not substantially affect the activity of other peptidases involved in formation and degradation of angiotensin-(1-7). Researchers should refrain from calling DIZE an ACE2 activator. Other mechanisms are responsible for the therapeutic benefits attributed to DIZE.
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Affiliation(s)
- Shiva Hadi Esfahani
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas
| | - Srinidhi Jayaraman
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas
| | - Vardan T Karamyan
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas
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21
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Diminazene aceturate attenuates hepatic ischemia/reperfusion injury in mice. Sci Rep 2022; 12:18158. [PMID: 36307457 PMCID: PMC9616812 DOI: 10.1038/s41598-022-21865-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 10/04/2022] [Indexed: 12/31/2022] Open
Abstract
Hepatic ischemia/reperfusion (I/R) injury is one of the leading causes of mortality following partial hepatectomy, liver transplantation, hypovolemic shock and trauma; however, effective therapeutic targets for the treatment of hepatic I/R injury are lacking. Recent studies have shown that diminazene aceturate (DIZE) has protective effects against inflammation, oxidative stress and cell death, which are the main pathogenetic mechanisms associated with hepatic I/R injury. However, the mechanistic effects DIZE exerts on hepatic I/R remain unknown. C57BL/6 male mice were pretreated with either 15 mg/kg DIZE or vehicle control (saline) and subjected to partial liver ischemia for 60 min. One day after induction of hepatic I/R, liver damage, inflammatory responses, oxidative stress and apoptosis were analyzed. By evaluating plasma alanine aminotransferase levels and histology, we found that DIZE treatment attenuated liver failure and was associated with a reduction in histologically-apparent liver damage. We also found that DIZE-treated mice had milder inflammatory responses, less reactive oxidative damage and less apoptosis following hepatic I/R compared to vehicle-treated mice. Taken together, our study demonstrates that DIZE protects against ischemic liver injury by attenuating inflammation and oxidative damage and may be a potential therapeutic agent for the prevention and treatment of ischemic liver failure.
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22
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Steckelings UM, Widdop RE, Sturrock ED, Lubbe L, Hussain T, Kaschina E, Unger T, Hallberg A, Carey RM, Sumners C. The Angiotensin AT 2 Receptor: From a Binding Site to a Novel Therapeutic Target. Pharmacol Rev 2022; 74:1051-1135. [PMID: 36180112 PMCID: PMC9553111 DOI: 10.1124/pharmrev.120.000281] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 05/19/2022] [Accepted: 06/27/2022] [Indexed: 11/22/2022] Open
Abstract
Discovered more than 30 years ago, the angiotensin AT2 receptor (AT2R) has evolved from a binding site with unknown function to a firmly established major effector within the protective arm of the renin-angiotensin system (RAS) and a target for new drugs in development. The AT2R represents an endogenous protective mechanism that can be manipulated in the majority of preclinical models to alleviate lung, renal, cardiovascular, metabolic, cutaneous, and neural diseases as well as cancer. This article is a comprehensive review summarizing our current knowledge of the AT2R, from its discovery to its position within the RAS and its overall functions. This is followed by an in-depth look at the characteristics of the AT2R, including its structure, intracellular signaling, homo- and heterodimerization, and expression. AT2R-selective ligands, from endogenous peptides to synthetic peptides and nonpeptide molecules that are used as research tools, are discussed. Finally, we summarize the known physiological roles of the AT2R and its abundant protective effects in multiple experimental disease models and expound on AT2R ligands that are undergoing development for clinical use. The present review highlights the controversial aspects and gaps in our knowledge of this receptor and illuminates future perspectives for AT2R research. SIGNIFICANCE STATEMENT: The angiotensin AT2 receptor (AT2R) is now regarded as a fully functional and important component of the renin-angiotensin system, with the potential of exerting protective actions in a variety of diseases. This review provides an in-depth view of the AT2R, which has progressed from being an enigma to becoming a therapeutic target.
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Affiliation(s)
- U Muscha Steckelings
- Institute of Molecular Medicine, Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark (U.M.S.); Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria, Australia (R.E.W.); Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa (E.D.S., L.L.); Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas (T.H.); Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Pharmacology, Cardiovascular-Metabolic-Renal (CMR) Research Center, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (E.K.); CARIM - School for Cardiovascular Diseases, Maastricht University, The Netherlands (T.U.); Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden (A.H.); Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia (R.M.C.); and Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida (C.S.)
| | - Robert E Widdop
- Institute of Molecular Medicine, Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark (U.M.S.); Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria, Australia (R.E.W.); Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa (E.D.S., L.L.); Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas (T.H.); Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Pharmacology, Cardiovascular-Metabolic-Renal (CMR) Research Center, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (E.K.); CARIM - School for Cardiovascular Diseases, Maastricht University, The Netherlands (T.U.); Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden (A.H.); Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia (R.M.C.); and Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida (C.S.)
| | - Edward D Sturrock
- Institute of Molecular Medicine, Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark (U.M.S.); Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria, Australia (R.E.W.); Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa (E.D.S., L.L.); Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas (T.H.); Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Pharmacology, Cardiovascular-Metabolic-Renal (CMR) Research Center, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (E.K.); CARIM - School for Cardiovascular Diseases, Maastricht University, The Netherlands (T.U.); Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden (A.H.); Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia (R.M.C.); and Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida (C.S.)
| | - Lizelle Lubbe
- Institute of Molecular Medicine, Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark (U.M.S.); Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria, Australia (R.E.W.); Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa (E.D.S., L.L.); Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas (T.H.); Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Pharmacology, Cardiovascular-Metabolic-Renal (CMR) Research Center, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (E.K.); CARIM - School for Cardiovascular Diseases, Maastricht University, The Netherlands (T.U.); Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden (A.H.); Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia (R.M.C.); and Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida (C.S.)
| | - Tahir Hussain
- Institute of Molecular Medicine, Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark (U.M.S.); Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria, Australia (R.E.W.); Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa (E.D.S., L.L.); Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas (T.H.); Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Pharmacology, Cardiovascular-Metabolic-Renal (CMR) Research Center, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (E.K.); CARIM - School for Cardiovascular Diseases, Maastricht University, The Netherlands (T.U.); Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden (A.H.); Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia (R.M.C.); and Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida (C.S.)
| | - Elena Kaschina
- Institute of Molecular Medicine, Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark (U.M.S.); Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria, Australia (R.E.W.); Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa (E.D.S., L.L.); Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas (T.H.); Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Pharmacology, Cardiovascular-Metabolic-Renal (CMR) Research Center, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (E.K.); CARIM - School for Cardiovascular Diseases, Maastricht University, The Netherlands (T.U.); Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden (A.H.); Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia (R.M.C.); and Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida (C.S.)
| | - Thomas Unger
- Institute of Molecular Medicine, Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark (U.M.S.); Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria, Australia (R.E.W.); Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa (E.D.S., L.L.); Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas (T.H.); Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Pharmacology, Cardiovascular-Metabolic-Renal (CMR) Research Center, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (E.K.); CARIM - School for Cardiovascular Diseases, Maastricht University, The Netherlands (T.U.); Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden (A.H.); Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia (R.M.C.); and Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida (C.S.)
| | - Anders Hallberg
- Institute of Molecular Medicine, Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark (U.M.S.); Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria, Australia (R.E.W.); Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa (E.D.S., L.L.); Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas (T.H.); Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Pharmacology, Cardiovascular-Metabolic-Renal (CMR) Research Center, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (E.K.); CARIM - School for Cardiovascular Diseases, Maastricht University, The Netherlands (T.U.); Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden (A.H.); Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia (R.M.C.); and Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida (C.S.)
| | - Robert M Carey
- Institute of Molecular Medicine, Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark (U.M.S.); Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria, Australia (R.E.W.); Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa (E.D.S., L.L.); Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas (T.H.); Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Pharmacology, Cardiovascular-Metabolic-Renal (CMR) Research Center, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (E.K.); CARIM - School for Cardiovascular Diseases, Maastricht University, The Netherlands (T.U.); Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden (A.H.); Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia (R.M.C.); and Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida (C.S.)
| | - Colin Sumners
- Institute of Molecular Medicine, Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark (U.M.S.); Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria, Australia (R.E.W.); Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa (E.D.S., L.L.); Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas (T.H.); Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Pharmacology, Cardiovascular-Metabolic-Renal (CMR) Research Center, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (E.K.); CARIM - School for Cardiovascular Diseases, Maastricht University, The Netherlands (T.U.); Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden (A.H.); Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia (R.M.C.); and Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida (C.S.)
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23
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Kale A, Shelke V, Sankrityayan H, Dagar N, Gaikwad AB. Klotho restoration via ACE2 activation: A potential therapeutic strategy against acute kidney injury-diabetes comorbidity. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166532. [PMID: 36041714 DOI: 10.1016/j.bbadis.2022.166532] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 08/03/2022] [Accepted: 08/22/2022] [Indexed: 10/15/2022]
Abstract
Acute kidney injury (AKI) is a collection of clinical syndromes with persistent increases in morbidity and mortality rates. Hyperglycemia is a risk factor for AKI development. Renin-angiotensin-aldosterone system (RAS) disequilibrium and Klotho downregulation also play a pivotal role in the pathogenesis of AKI. Moreover, the relationship between Klotho and ACE2 (a component of non-conventional RAS) regulation in AKI remains an unexplored area of research. Hence, in this study, we investigated ACE2 and Klotho regulation in AKI using ischemic Wistar rats and NRK52E cells under normal and hyperglycemic conditions. Our findings suggested that hyperglycemia exacerbates renal ischemia-reperfusion injury (IRI)/hypoxia-reperfusion injury (HRI) induced AKI. Systemic and renal Klotho deficiency is a novel hallmark of AKI. Additionally, ACE2 is a protective component of the RAS, and its inhibition/deficiency leads to inflammation, apoptosis, Klotho downregulation, and thus AKI development. However, ACE2 activation resulted in the amelioration of AKI. Importantly, ACE2 plays an important role in Klotho upregulation, which might act as an intermediate for ACE2-mediated reno-protection. In conclusion, ACE2 activator i.e. DIZE restored endogenous ACE2-Ang-(1-7)-Klotho level, inhibited apoptosis and inflammation, and ameliorates IRI/HRI induced AKI under diabetic and non-diabetic conditions. Hence, in future, targeting ACE2-Ang-(1-7)-Klotho axis may prove a novel therapeutic strategy against AKI, where further preclinical and clinical investigations are required to verify the clinical potential of this finding.
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Affiliation(s)
- Ajinath Kale
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, Rajasthan 333031, India
| | - Vishwadeep Shelke
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, Rajasthan 333031, India
| | - Himanshu Sankrityayan
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, Rajasthan 333031, India
| | - Neha Dagar
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, Rajasthan 333031, India
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, Rajasthan 333031, India.
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24
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Matsoukas JM, Gadanec LK, Zulli A, Apostolopoulos V, Kelaidonis K, Ligielli I, Moschovou K, Georgiou N, Plotas P, Chasapis CT, Moore G, Ridgway H, Mavromoustakos T. Diminazene Aceturate Reduces Angiotensin II Constriction and Interacts with the Spike Protein of Severe Acute Respiratory Syndrome Coronavirus 2. Biomedicines 2022; 10:biomedicines10071731. [PMID: 35885036 PMCID: PMC9312513 DOI: 10.3390/biomedicines10071731] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/27/2022] [Accepted: 07/05/2022] [Indexed: 12/15/2022] Open
Abstract
Diminazene aceturate (DIZE) is a putative angiotensin-converting enzyme 2 (ACE2) activator and angiotensin type 1 receptor antagonist (AT1R). Its simple chemical structure possesses a negatively charged triazene segment that is homologous to the tetrazole of angiotensin receptor blockers (ARB), which explains its AT1R antagonistic activity. Additionally, the activation of ACE2 by DIZE converts the toxic octapeptide angiotensin II (AngII) to the heptapeptides angiotensin 1–7 and alamandine, which promote vasodilation and maintains homeostatic balance. Due to DIZE’s protective cardiovascular and pulmonary effects and its ability to target ACE2 (the predominant receptor utilized by severe acute respiratory syndrome coronavirus 2 to enter host cells), it is a promising treatment for coronavirus 2019 (COVID-19). To determine DIZE’s ability to inhibit AngII constriction, in vitro isometric tension analysis was conducted on rabbit iliac arteries incubated with DIZE or candesartan and constricted with cumulative doses of AngII. In silico docking and ligand interaction studies were performed to investigate potential interactions between DIZE and other ARBs with AT1R and the spike protein/ACE2 complex. DIZE, similar to the other ARBs investigated, was able to abolish vasoconstriction in response to AngII and exhibited a binding affinity for the spike protein/ACE2 complex (PDB 6LZ6). These results support the potential of DIZE as a treatment for COVID-19.
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Affiliation(s)
- John M. Matsoukas
- NewDrug PC, Patras Science Park, 26500 Patras, Greece;
- Institute for Health and Sport, Victoria University, Melbourne, VIC 3030, Australia; (L.K.G.); (A.Z.); (V.A.)
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
- Correspondence: (J.M.M.); (T.M.)
| | - Laura Kate Gadanec
- Institute for Health and Sport, Victoria University, Melbourne, VIC 3030, Australia; (L.K.G.); (A.Z.); (V.A.)
| | - Anthony Zulli
- Institute for Health and Sport, Victoria University, Melbourne, VIC 3030, Australia; (L.K.G.); (A.Z.); (V.A.)
| | - Vasso Apostolopoulos
- Institute for Health and Sport, Victoria University, Melbourne, VIC 3030, Australia; (L.K.G.); (A.Z.); (V.A.)
- Immunology Program, Australian Institute for Musculoskeletal Science, Melbourne, VIC 3021, Australia
| | | | - Irene Ligielli
- Department of Chemistry National and Kapodistrian, University of Athens, Zographou, 15784 Athens, Greece; (I.L.); (K.M.); (N.G.)
| | - Kalliopi Moschovou
- Department of Chemistry National and Kapodistrian, University of Athens, Zographou, 15784 Athens, Greece; (I.L.); (K.M.); (N.G.)
| | - Nikitas Georgiou
- Department of Chemistry National and Kapodistrian, University of Athens, Zographou, 15784 Athens, Greece; (I.L.); (K.M.); (N.G.)
| | - Panagiotis Plotas
- Laboratory of Primary Health Care, School of Health Rehabilitation Sciences, University of Patras, 26504 Patras, Greece;
| | - Christos T. Chasapis
- NMR Facility, Instrumental Analysis Laboratory, School of Natural Sciences, University of Patras, 26504 Patras, Greece;
- Institute of Chemical Engineering Sciences, Foundation for Research and Technology, Hellas (FORTH/ICE-HT), 26504 Patras, Greece
| | - Graham Moore
- Pepmetics Incorporated, 772 Murphy Pace, Victoria, BC V8Y 3H4, Canada;
| | - Harry Ridgway
- Institute for Sustainable Industries and Liveable Cities, Victoria University, Melbourne, VIC 8001, Australia;
- AquaMem Consultants, Rodeo, NM 88056, USA
| | - Thomas Mavromoustakos
- Department of Chemistry National and Kapodistrian, University of Athens, Zographou, 15784 Athens, Greece; (I.L.); (K.M.); (N.G.)
- Correspondence: (J.M.M.); (T.M.)
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25
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Li Z, Peng M, Chen P, Liu C, Hu A, Zhang Y, Peng J, Liu J, Li Y, Li W, Zhu W, Guan D, Zhang Y, Chen H, Li J, Fan D, Huang K, Lin F, Zhang Z, Guo Z, Luo H, He X, Zhu Y, Li L, Huang B, Cai W, Gu L, Lu Y, Deng K, Yan L, Chen S. Imatinib and methazolamide ameliorate COVID-19-induced metabolic complications via elevating ACE2 enzymatic activity and inhibiting viral entry. Cell Metab 2022; 34:424-440.e7. [PMID: 35150639 PMCID: PMC8832557 DOI: 10.1016/j.cmet.2022.01.008] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 11/22/2021] [Accepted: 01/20/2022] [Indexed: 02/07/2023]
Abstract
Coronavirus disease 2019 (COVID-19) represents a systemic disease that may cause severe metabolic complications in multiple tissues including liver, kidney, and cardiovascular system. However, the underlying mechanisms and optimal treatment remain elusive. Our study shows that impairment of ACE2 pathway is a key factor linking virus infection to its secondary metabolic sequelae. By using structure-based high-throughput virtual screening and connectivity map database, followed with experimental validations, we identify imatinib, methazolamide, and harpagoside as direct enzymatic activators of ACE2. Imatinib and methazolamide remarkably improve metabolic perturbations in vivo in an ACE2-dependent manner under the insulin-resistant state and SARS-CoV-2-infected state. Moreover, viral entry is directly inhibited by these three compounds due to allosteric inhibition of ACE2 binding to spike protein on SARS-CoV-2. Taken together, our study shows that enzymatic activation of ACE2 via imatinib, methazolamide, or harpagoside may be a conceptually new strategy to treat metabolic sequelae of COVID-19.
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Affiliation(s)
- Zilun Li
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
| | - Meixiu Peng
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
| | - Pin Chen
- National Supercomputer Center in Guangzhou, School of Computer Science and Engineering, Sun Yat-Sen University, Guangzhou, Guangdong 510006, China
| | - Chenshu Liu
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
| | - Ao Hu
- Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; Department of Immunology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
| | - Yixin Zhang
- Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; Department of Immunology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
| | - Jiangyun Peng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Jiang Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Yihui Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Wenxue Li
- Guangzhou Center for Disease Control and Prevention, Guangzhou, Guangdong 510440, China
| | - Wei Zhu
- Guangzhou Center for Disease Control and Prevention, Guangzhou, Guangdong 510440, China
| | - Dongxian Guan
- Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Yang Zhang
- School of Public Health, Sun Yat-Sen University, Shenzhen, Guangdong 518107, China
| | - Hongyin Chen
- School of Public Health, Sun Yat-Sen University, Shenzhen, Guangdong 518107, China
| | - Jiuzhou Li
- School of Public Health, Sun Yat-Sen University, Shenzhen, Guangdong 518107, China
| | - Dongxiao Fan
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
| | - Kan Huang
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
| | - Fen Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Zefeng Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Zeling Guo
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
| | - Hengli Luo
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Xi He
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China
| | - Yuanyuan Zhu
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China
| | - Linghua Li
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China
| | - Bingding Huang
- College of Big Data and Internet, Shenzhen Technology University, Shenzhen, Guangdong 518118, China
| | - Weikang Cai
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, NY 11568, USA
| | - Lei Gu
- Max Planck Institute for Heart and Lung Research and Cardiopulmonary Institute (CPI), Bad Nauheim 61231, Germany
| | - Yutong Lu
- National Supercomputer Center in Guangzhou, School of Computer Science and Engineering, Sun Yat-Sen University, Guangzhou, Guangdong 510006, China
| | - Kai Deng
- Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; Department of Immunology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
| | - Li Yan
- Department of Endocrinology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China.
| | - Sifan Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China.
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26
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Sankrityayan H, Kale A, Gaikwad AB. Inhibition of endoplasmic reticulum stress combined with activation of angiotensin-converting enzyme 2: novel approach for the prevention of endothelial dysfunction in type 1 diabetic rats. Can J Physiol Pharmacol 2022; 100:234-239. [PMID: 34587465 DOI: 10.1139/cjpp-2021-0170] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Persistent hyperglycemia in type 1 diabetes triggers numerous signaling pathways, which may prove deleterious to the endothelium. As hyperglycemia damages the endothelial layer via multiple signaling pathways, including enhanced oxidative stress, downregulation of angiotensin-converting enzyme 2 signaling, and exacerbation of endoplasmic reticulum (ER) stress, it becomes difficult to prevent injury using monotherapy. Thus, the present study was conceived to evaluate the combined effect of ER stress inhibition along with angiotensin-converting enzyme 2 activation, two major contributors to hyperglycemia-induced endothelial dysfunction, in preventing endothelial dysfunction associated with type 1 diabetes. Streptozotocin-induced diabetic animals were treated with either diminazene aceturate (5 mg·kg-1 per day, p.o.) or tauroursodeoxycholic acid, sodium salt (200 mg·kg-1 per day i.p.), or both for 4 weeks. Endothelial dysfunction was evaluated using vasoreactivity assay, where acetylcholine-induced relaxation was assessed in phenylephrine pre-contracted rings. Combination therapy significantly improved vascular relaxation when compared with diabetic control as well as monotherapy. Restoration of nitrite levels along with prevention of collagen led to improved vasodilatation. Moreover, there was an overall reduction in aortic oxidative stress. We conclude that by simultaneously inhibiting ER stress and activating angiotensin-converting enzyme 2 deleterious effects of hyperglycemia on endothelium were significantly alleviated. This could serve as a novel strategy for the prevention of endothelial dysfunction.
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Affiliation(s)
- Himanshu Sankrityayan
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan 333031, India
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan 333031, India
| | - Ajinath Kale
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan 333031, India
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan 333031, India
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan 333031, India
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan 333031, India
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Esfahani SH, Karamyan VT. Challenges with the proposed ACE2 activation mechanism of diminazene aceturate. Clin Exp Pharmacol Physiol 2022; 49:608-610. [PMID: 35199858 DOI: 10.1111/1440-1681.13636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 02/09/2022] [Indexed: 11/30/2022]
Affiliation(s)
- Shiva Hadi Esfahani
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas, USA
| | - Vardan T Karamyan
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas, USA.,Center for Blood Brain Barrier Research, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, USA
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28
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Oyagbemi AA, Ajibade TO, Aboua YG, Gbadamosi IT, Adedapo ADA, Aro AO, Adejumobi OA, Thamahane-Katengua E, Omobowale TO, Falayi OO, Oyagbemi TO, Ogunpolu BS, Hassan FO, Ogunmiluyi IO, Ola-Davies OE, Saba AB, Adedapo AA, Nkadimeng SM, McGaw LJ, Kayoka-Kabongo PN, Yakubu MA, Oguntibeju OO. The therapeutic potential of the novel angiotensin-converting enzyme 2 in the treatment of coronavirus disease-19. Vet World 2021; 14:2705-2713. [PMID: 34903929 PMCID: PMC8654738 DOI: 10.14202/vetworld.2021.2705-2713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 09/13/2021] [Indexed: 01/08/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of coronavirus disease 2019 (COVID-19). This virus has become a global pandemic with unprecedented mortality and morbidity along with attendant financial and economic crises. Furthermore, COVID-19 can easily be transmitted regardless of religion, race, sex, or status. Globally, high hospitalization rates of COVID-19 patients have been reported, and billions of dollars have been spent to contain the pandemic. Angiotensin-converting enzyme (ACE) 2 is a receptor of SARS-CoV-2, which has a significant role in the entry of the virus into the host cell. ACE2 is highly expressed in the type II alveolar cells of the lungs, upper esophagus, stratified epithelial cells, and other tissues in the body. The diminished expressions of ACE2 have been associated with hypertension, arteriosclerosis, heart failure, chronic kidney disease, and immune system dysregulation. Overall, the potential drug candidates that could serve as ACE2 activators or enhance the expression of ACE2 in a disease state, such as COVID-19, hold considerable promise in mitigating the COVID-19 pandemic. This study reviews the therapeutic potential and pharmacological benefits of the novel ACE2 in the management of COVID-19 using search engines, such as Google, Scopus, PubMed, and PubMed Central.
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Affiliation(s)
- Ademola Adetokunbo Oyagbemi
- Department of Veterinary Physiology and Biochemistry, Faculty of Veterinary Medicine, University of Ibadan, Nigeria
| | - Temitayo Olabisi Ajibade
- Department of Veterinary Physiology and Biochemistry, Faculty of Veterinary Medicine, University of Ibadan, Nigeria
| | - Yapo Guillaume Aboua
- Department of Health Sciences, Faculty of Health and Applied Sciences, Namibia University of Science and Technology, Private Bag 13388, Namibia
| | | | | | - Abimbola Obemisola Aro
- Department of Agriculture and Animal Health, College of Agriculture and Environmental Sciences, University of South Africa, Florida, South Africa
| | | | - Emma Thamahane-Katengua
- Department of Health Information Management, Botho University, Faculty of Health and Education, Botswana
| | | | - Olufunke Olubunmi Falayi
- Department of Veterinary Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Ibadan, Nigeria
| | - Taiwo Olaide Oyagbemi
- Department of Veterinary Parasitology and Entomology, Faculty of Veterinary Medicine, University of Ibadan, Nigeria
| | | | - Fasilat Oluwakemi Hassan
- Department of Veterinary Physiology and Biochemistry, Faculty of Veterinary Medicine, University of Ibadan, Nigeria
| | | | - Olufunke Eunice Ola-Davies
- Department of Veterinary Physiology and Biochemistry, Faculty of Veterinary Medicine, University of Ibadan, Nigeria
| | - Adebowale Benard Saba
- Department of Veterinary Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Ibadan, Nigeria
| | - Adeolu Alex Adedapo
- Department of Veterinary Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Ibadan, Nigeria
| | - Sanah Malomile Nkadimeng
- Department of Paraclinical Science, Phytomedicine Programme, University of Pretoria, Faculty of Veterinary Science, Old Soutpan Road, Onderstepoort, 0110, South Africa
| | - Lyndy Joy McGaw
- Department of Paraclinical Science, Phytomedicine Programme, University of Pretoria, Faculty of Veterinary Science, Old Soutpan Road, Onderstepoort, 0110, South Africa
| | - Prudence Ngalula Kayoka-Kabongo
- Department of Agriculture and Animal Health, College of Agriculture and Environmental Sciences, University of South Africa, Florida, South Africa
| | - Momoh Audu Yakubu
- Department of Environmental and Interdisciplinary Sciences, College of Science, Engineering and Technology, Vascular Biology Unit, Center for Cardiovascular Diseases, Texas Southern University, Houston, TX, USA
| | - Oluwafemi Omoniyi Oguntibeju
- Department of Biomedical Sciences, Phytomedicine and Phytochemistry Group, Oxidative Stress Research Centre, Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, Bellville 7535, South Africa
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29
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Lapi D, Cammalleri M, Dal Monte M, Di Maro M, Santillo M, Belfiore A, Nasti G, Damiano S, Trio R, Chiurazzi M, De Conno B, Serao N, Mondola P, Colantuoni A, Guida B. The Effects of Angiotensin II or Angiotensin 1-7 on Rat Pial Microcirculation during Hypoperfusion and Reperfusion Injury: Role of Redox Stress. Biomolecules 2021; 11:biom11121861. [PMID: 34944506 PMCID: PMC8699607 DOI: 10.3390/biom11121861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 12/03/2021] [Accepted: 12/08/2021] [Indexed: 11/16/2022] Open
Abstract
Renin-angiotensin systems produce angiotensin II (Ang II) and angiotensin 1-7 (Ang 1-7), which are able to induce opposite effects on circulation. This study in vivo assessed the effects induced by Ang II or Ang 1-7 on rat pial microcirculation during hypoperfusion-reperfusion, clarifying the mechanisms causing the imbalance between Ang II and Ang 1-7. The fluorescence microscopy was used to quantify the microvascular parameters. Hypoperfusion and reperfusion caused vasoconstriction, disruption of blood-brain barrier, reduction of capillary perfusion and an increase in reactive oxygen species production. Rats treated with Ang II showed exacerbated microvascular damage with stronger vasoconstriction compared to hypoperfused rats, a further increase in leakage, higher decrease in capillary perfusion and marker oxidative stress. Candesartan cilexetil (specific Ang II type 1 receptor (AT1R) antagonist) administration prior to Ang II prevented the effects induced by Ang II, blunting the hypoperfusion-reperfusion injury. Ang 1-7 or ACE2 activator administration, preserved the pial microcirculation from hypoperfusion-reperfusion damage. These effects of Ang 1-7 were blunted by a Mas (Mas oncogene-encoded protein) receptor antagonist, while Ang II type 2 receptor antagonists did not affect Ang 1-7-induced changes. In conclusion, Ang II and Ang 1-7 triggered different mechanisms through AT1R or MAS receptors able to affect cerebral microvascular injury.
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Affiliation(s)
- Dominga Lapi
- Department of Biology, University of Pisa, Via San Zeno, 31, 56127 Pisa, Italy; (M.C.); (M.D.M.)
- Correspondence: ; Tel.: +39-050-2211433
| | - Maurizio Cammalleri
- Department of Biology, University of Pisa, Via San Zeno, 31, 56127 Pisa, Italy; (M.C.); (M.D.M.)
| | - Massimo Dal Monte
- Department of Biology, University of Pisa, Via San Zeno, 31, 56127 Pisa, Italy; (M.C.); (M.D.M.)
| | - Martina Di Maro
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Via S. Pansini, 5, 80131 Naples, Italy; (M.D.M.); (M.S.); (A.B.); (G.N.); (S.D.); (R.T.); (M.C.); (B.D.C.); (N.S.); (P.M.); (A.C.); (B.G.)
| | - Mariarosaria Santillo
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Via S. Pansini, 5, 80131 Naples, Italy; (M.D.M.); (M.S.); (A.B.); (G.N.); (S.D.); (R.T.); (M.C.); (B.D.C.); (N.S.); (P.M.); (A.C.); (B.G.)
| | - Anna Belfiore
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Via S. Pansini, 5, 80131 Naples, Italy; (M.D.M.); (M.S.); (A.B.); (G.N.); (S.D.); (R.T.); (M.C.); (B.D.C.); (N.S.); (P.M.); (A.C.); (B.G.)
| | - Gilda Nasti
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Via S. Pansini, 5, 80131 Naples, Italy; (M.D.M.); (M.S.); (A.B.); (G.N.); (S.D.); (R.T.); (M.C.); (B.D.C.); (N.S.); (P.M.); (A.C.); (B.G.)
| | - Simona Damiano
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Via S. Pansini, 5, 80131 Naples, Italy; (M.D.M.); (M.S.); (A.B.); (G.N.); (S.D.); (R.T.); (M.C.); (B.D.C.); (N.S.); (P.M.); (A.C.); (B.G.)
| | - Rossella Trio
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Via S. Pansini, 5, 80131 Naples, Italy; (M.D.M.); (M.S.); (A.B.); (G.N.); (S.D.); (R.T.); (M.C.); (B.D.C.); (N.S.); (P.M.); (A.C.); (B.G.)
| | - Martina Chiurazzi
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Via S. Pansini, 5, 80131 Naples, Italy; (M.D.M.); (M.S.); (A.B.); (G.N.); (S.D.); (R.T.); (M.C.); (B.D.C.); (N.S.); (P.M.); (A.C.); (B.G.)
| | - Barbara De Conno
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Via S. Pansini, 5, 80131 Naples, Italy; (M.D.M.); (M.S.); (A.B.); (G.N.); (S.D.); (R.T.); (M.C.); (B.D.C.); (N.S.); (P.M.); (A.C.); (B.G.)
| | - Nicola Serao
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Via S. Pansini, 5, 80131 Naples, Italy; (M.D.M.); (M.S.); (A.B.); (G.N.); (S.D.); (R.T.); (M.C.); (B.D.C.); (N.S.); (P.M.); (A.C.); (B.G.)
| | - Paolo Mondola
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Via S. Pansini, 5, 80131 Naples, Italy; (M.D.M.); (M.S.); (A.B.); (G.N.); (S.D.); (R.T.); (M.C.); (B.D.C.); (N.S.); (P.M.); (A.C.); (B.G.)
| | - Antonio Colantuoni
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Via S. Pansini, 5, 80131 Naples, Italy; (M.D.M.); (M.S.); (A.B.); (G.N.); (S.D.); (R.T.); (M.C.); (B.D.C.); (N.S.); (P.M.); (A.C.); (B.G.)
| | - Bruna Guida
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Via S. Pansini, 5, 80131 Naples, Italy; (M.D.M.); (M.S.); (A.B.); (G.N.); (S.D.); (R.T.); (M.C.); (B.D.C.); (N.S.); (P.M.); (A.C.); (B.G.)
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Gupta D, Kumar A, Mandloi A, Shenoy V. Renin angiotensin aldosterone system in pulmonary fibrosis: Pathogenesis to therapeutic possibilities. Pharmacol Res 2021; 174:105924. [PMID: 34607005 DOI: 10.1016/j.phrs.2021.105924] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 09/21/2021] [Accepted: 09/29/2021] [Indexed: 01/12/2023]
Abstract
Pulmonary fibrosis is a devastating lung disease with multifactorial etiology characterized by alveolar injury, fibroblast proliferation and excessive deposition of extracellular matrix proteins, which progressively results in respiratory failure and death. Accumulating evidence from experimental and clinical studies supports a central role of the renin angiotensin aldosterone system (RAAS) in the pathogenesis and progression of idiopathic pulmonary fibrosis. Angiotensin II (Ang II), a key vasoactive peptide of the RAAS mediates pro-inflammatory and pro-fibrotic effects on the lungs, adversely affecting organ function. Recent years have witnessed seminal discoveries in the field of RAAS. Identification of new enzymes, peptides and receptors has led to the development of several novel concepts. Of particular interest is the establishment of a protective axis of the RAAS comprising of Angiotensin converting enzyme 2 (ACE2), Angiotensin-(1-7) [Ang-(1-7)], and the Mas receptor (the ACE2/Ang-(1-7)/Mas axis), and the discovery of a functional role for the Angiotensin type 2 (AT2) receptor. Herein, we will review our current understanding of the role of RAAS in lung fibrogenesis, provide evidence on the anti-fibrotic actions of the newly recognized RAAS components (the ACE2/Ang-(1-7)/Mas axis and AT2 receptor), discuss potential strategies and translational efforts to convert this new knowledge into effective therapeutics for PF.
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Affiliation(s)
- Dipankar Gupta
- Congenital Heart Center, Department of Pediatrics, University of Florida, College of Medicine, Gainesville, FL, USA
| | - Ashok Kumar
- Department of Internal Medicine, Kansas University Medical Center, Kansas City, KS, USA
| | - Avinash Mandloi
- College of Pharmacy, VNS Group of Institutions, Bhopal, India
| | - Vinayak Shenoy
- College of Pharmacy, California Health Sciences University, Clovis, CA, USA.
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Liu LP, Zhang XL, Li J. New perspectives on angiotensin-converting enzyme 2 and its related diseases. World J Diabetes 2021; 12:839-854. [PMID: 34168732 PMCID: PMC8192247 DOI: 10.4239/wjd.v12.i6.839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/30/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Since the worldwide outbreak of coronavirus disease 2019, angiotensin-converting enzyme 2 (ACE2) has received widespread attention as the cell receptor of the severe acute respiratory syndrome coronavirus 2 virus. At the same time, as a key enzyme in the renin-angiotensin-system, ACE2 is considered to be an endogenous negative regulator of vasoconstriction, proliferation, fibrosis, and proinflammation caused by the ACE-angiotensin II-angiotensin type 1 receptor axis. ACE2 is now implicated as being closely connected to diabetes, cardiovascular, kidney, and lung diseases, and so on. This review covers the available information on the host factors regulating ACE2 and discusses its role in a variety of pathophysiological conditions in animal models and humans.
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Affiliation(s)
- Li-Ping Liu
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, School of Medicine, Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Xiao-Li Zhang
- TheFifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg 68135, Baden-Württemberg, Germany
| | - Jian Li
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, School of Medicine, Hunan Normal University, Changsha 410013, Hunan Province, China
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32
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Oz M, Lorke DE. Multifunctional angiotensin converting enzyme 2, the SARS-CoV-2 entry receptor, and critical appraisal of its role in acute lung injury. Biomed Pharmacother 2021; 136:111193. [PMID: 33461019 PMCID: PMC7836742 DOI: 10.1016/j.biopha.2020.111193] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 12/15/2020] [Accepted: 12/26/2020] [Indexed: 12/11/2022] Open
Abstract
The recent emergence of coronavirus disease-2019 (COVID-19) as a pandemic affecting millions of individuals has raised great concern throughout the world, and the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was identified as the causative agent for COVID-19. The multifunctional protein angiotensin converting enzyme 2 (ACE2) is accepted as its primary target for entry into host cells. In its enzymatic function, ACE2, like its homologue ACE, regulates the renin-angiotensin system (RAS) critical for cardiovascular and renal homeostasis in mammals. Unlike ACE, however, ACE2 drives an alternative RAS pathway by degrading Ang-II and thus operates to balance RAS homeostasis in the context of hypertension, heart failure, and cardiovascular as well as renal complications of diabetes. Outside the RAS, ACE2 hydrolyzes key peptides, such as amyloid-β, apelin, and [des-Arg9]-bradykinin. In addition to its enzymatic functions, ACE2 is found to regulate intestinal amino acid homeostasis and the gut microbiome. Although the non-enzymatic function of ACE2 as the entry receptor for SARS-CoV-2 has been well established, the contribution of enzymatic functions of ACE2 to the pathogenesis of COVID-19-related lung injury has been a matter of debate. A complete understanding of this central enzyme may begin to explain the various symptoms and pathologies seen in SARS-CoV-2 infected individuals, and may aid in the development of novel treatments for COVID-19.
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Affiliation(s)
- Murat Oz
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Safat 13110, Kuwait.
| | - Dietrich Ernst Lorke
- Department of Anatomy and Cellular Biology, Khalifa University, Abu Dhabi, United Arab Emirates; Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
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ACE2 activator diminazene aceturate exerts renoprotective effects in gentamicin-induced acute renal injury in rats. Clin Sci (Lond) 2021; 134:3093-3106. [PMID: 33206153 DOI: 10.1042/cs20201022] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 11/16/2020] [Accepted: 11/18/2020] [Indexed: 12/13/2022]
Abstract
Acute Kidney Injury (AKI) comprises a rapidly developed renal failure and is associated with high mortality rates. The Renin-Angiotensin System (RAS) plays a pivotal role in AKI, as the over-active RAS axis exerts major deleterious effects in disease progression. In this sense, the conversion of Angiotensin II (Ang II) into Angiotensin-(1-7) (Ang-(1-7)) by the Angiotensin-converting enzyme 2 (ACE2) is of utmost importance to prevent worse clinical outcomes. Previous studies reported the beneficial effects of oral diminazene aceturate (DIZE) administration, an ACE2 activator, in renal diseases models. In the present study, we aimed to evaluate the therapeutic effects of DIZE administration in experimental AKI induced by gentamicin (GM) in rats. Our findings showed that treatment with DIZE improved renal function and tissue damage by increasing Ang-(1-7) and ACE2 activity, and reducing TNF-α. These results corroborate with a raising potential of ACE2 activation as a strategy for treating AKI.
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da Silva Oliveira GL, da Silva APDSCL. Evaluation of the non-clinical toxicity of an antiparasitic agent: diminazene aceturate. Drug Chem Toxicol 2021; 45:2003-2013. [PMID: 33685320 DOI: 10.1080/01480545.2021.1894741] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
The diminazene aceturate (C14H15N7.2C4H7NO3) is a chemotherapeutic agent with more than six decades of use, however more studies regarding its toxicity still need to be performed. Thus, the present study determined the acute toxicity (14 days) of diminazene acetate (DIZE) in male and female swiss mice by changes in body mass, food consumption, biochemical and hematological parameters, locomotor activity and motor coordination. DIZE was administered at a single dose (1000 and 2000 mg/kg) orally. In addition, in vitro antioxidant capacity, hemolytic activity, toxicity in Artemia salina and in silico evaluation were also performed. The results obtained include several signs of toxicity (hypoactivity, loss of the straightening reflex and tachycardia), reduction of behavioral activity (locomotor activity and motor coordination) and significant changes (p < 0.05) in biochemical and hematological parameters. According to the in silico study, the DIZE can be classified based on the mean lethal dose (LD50) in category 4 (300 mg/kg < LD50 ≤ 2000 mg/kg, ProTox-II) or 3 (50 mg/kg < LD50 ≤ 300 mg/kg, AdmetSAR 1.0). Additionally, DIZE (30.3-969.9 nM) was not toxic to A. salina in the first 48 hours of treatment and was not cytotoxic to rat red blood cells after induced hemolysis. In vitro results indicated low antioxidant capacity against DPPH• and ABTS•+ radicals. Therefore, DIZE induces several adverse effects with influence on the central nervous system, changes in hematological and biochemical parameters and even mortality at the highest dose. However, absence of toxicity was observed in A. salina and rats red blood cells.
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Souza LKM, Nogueira KM, Araújo TSL, Sousa NA, Sousa FBM, Oliveira AP, Sales T, Silva K, Rocha TM, Leal LKAM, Magalhães PJC, Souza MHLP, Medeiros JVR. Anti-diarrheal therapeutic potential of diminazene aceturate stimulation of the ACE II/Ang-(1-7)/Mas receptor axis in mice: A trial study. Biochem Pharmacol 2021; 186:114500. [PMID: 33684388 DOI: 10.1016/j.bcp.2021.114500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 02/17/2021] [Accepted: 02/26/2021] [Indexed: 11/17/2022]
Abstract
The angiotensin (Ang) II converting enzyme (ACE II) pathway has recently been shown to be associated with several beneficial effects on the body, especially on the cardiac system and gastrointestinal tract. ACE II is responsible for converting Ang II into the active peptide Ang-(1-7), which in turn binds to a metabotropic receptor, the Mas receptor (MasR). Recent studies have demonstrated that Diminazene Aceturate (DIZE), a trypanosomicide used in animals, activates the ACE II pathway. In this study, we aimed to evaluate the antidiarrheal effects promoted by the administration of DIZE to activate the ACE II/Ang-(1-7)/MasR axis in induced diarrhea mice models. The results show that activation of the ACE II pathway exerts antidiarrheal effects that reduce total diarrheal stools and enteropooling. In addition, it increases Na+/K+-ATPase activity and reduces gastrointestinal transit and thus inhibits contractions of intestinal smooth muscle; decreases transepithelial electrical resistance, epithelial permeability, PGE2-induced diarrhea, and proinflammatory cytokines; and increases anti-inflammatory cytokines. Enzyme-linked immunosorbent assay (ELISA) demonstrated that DIZE, when activating the ACE II/Ang-(1-7)/MasR axis, can still interact with GM1 receptors, which reduces cholera toxin-induced diarrhea. Therefore, activation of the ACE II/Ang-(1-7)/MasR axis can be an important pharmacological target for the treatment of diarrheal diseases.
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Affiliation(s)
- Luan K M Souza
- The Northeast Biotechnology Network (RENORBIO), Federal University of Piauí, Teresina, PI 64049-550, Brazil; Laboratory of Pharmacology of Inflammation and Gastrointestinal Disorders (Lafidg), Federal University of Parnaíba Delta (UFDPar), Av. São Sebastião, n° 2819, CEP 64202-02 Parnaíba, PI, Brazil.
| | - Kerolayne M Nogueira
- Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE 60430-275, Brazil
| | - Thiago S L Araújo
- The Northeast Biotechnology Network (RENORBIO), Federal University of Piauí, Teresina, PI 64049-550, Brazil; Laboratory of Pharmacology of Inflammation and Gastrointestinal Disorders (Lafidg), Federal University of Parnaíba Delta (UFDPar), Av. São Sebastião, n° 2819, CEP 64202-02 Parnaíba, PI, Brazil
| | - Nayara A Sousa
- The Northeast Biotechnology Network (RENORBIO), Federal University of Piauí, Teresina, PI 64049-550, Brazil; Laboratory of Pharmacology of Inflammation and Gastrointestinal Disorders (Lafidg), Federal University of Parnaíba Delta (UFDPar), Av. São Sebastião, n° 2819, CEP 64202-02 Parnaíba, PI, Brazil
| | - Francisca B M Sousa
- The Northeast Biotechnology Network (RENORBIO), Federal University of Piauí, Teresina, PI 64049-550, Brazil; Laboratory of Pharmacology of Inflammation and Gastrointestinal Disorders (Lafidg), Federal University of Parnaíba Delta (UFDPar), Av. São Sebastião, n° 2819, CEP 64202-02 Parnaíba, PI, Brazil
| | - Ana P Oliveira
- The Northeast Biotechnology Network (RENORBIO), Federal University of Piauí, Teresina, PI 64049-550, Brazil; Laboratory of Pharmacology of Inflammation and Gastrointestinal Disorders (Lafidg), Federal University of Parnaíba Delta (UFDPar), Av. São Sebastião, n° 2819, CEP 64202-02 Parnaíba, PI, Brazil
| | - Thiago Sales
- Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE 60430-275, Brazil
| | - Karine Silva
- Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE 60430-275, Brazil
| | - Talita M Rocha
- Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE 60430-275, Brazil
| | - Luzia K A M Leal
- Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE 60430-275, Brazil
| | - Pedro J C Magalhães
- Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE 60430-275, Brazil
| | - Marcellus H L P Souza
- Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE 60430-275, Brazil
| | - Jand V R Medeiros
- The Northeast Biotechnology Network (RENORBIO), Federal University of Piauí, Teresina, PI 64049-550, Brazil; Laboratory of Pharmacology of Inflammation and Gastrointestinal Disorders (Lafidg), Federal University of Parnaíba Delta (UFDPar), Av. São Sebastião, n° 2819, CEP 64202-02 Parnaíba, PI, Brazil; Biotechnology and Biodiversity Center Research, BIOTEC, Federal University of Parnaíba Delta, Parnaíba, PI 64202-020, Brazil
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Pathangey G, Fadadu PP, Hospodar AR, Abbas AE. Angiotensin-converting enzyme 2 and COVID-19: patients, comorbidities, and therapies. Am J Physiol Lung Cell Mol Physiol 2021; 320:L301-L330. [PMID: 33237815 PMCID: PMC7938645 DOI: 10.1152/ajplung.00259.2020] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 11/19/2020] [Accepted: 11/24/2020] [Indexed: 02/07/2023] Open
Abstract
On March 11, 2020, the World Health Organization declared coronavirus disease 2019 (COVID-19) a pandemic, and the reality of the situation has finally caught up to the widespread reach of the disease. The presentation of the disease is highly variable, ranging from asymptomatic carriers to critical COVID-19. The availability of angiotensin-converting enzyme 2 (ACE2) receptors may reportedly increase the susceptibility and/or disease progression of COVID-19. Comorbidities and risk factors have also been noted to increase COVID-19 susceptibility. In this paper, we hereby review the evidence pertaining to ACE2's relationship to common comorbidities, risk factors, and therapies associated with the susceptibility and severity of COVID-19. We also highlight gaps of knowledge that require further investigation. The primary comorbidities of respiratory disease, cardiovascular disease, renal disease, diabetes, obesity, and hypertension had strong evidence. The secondary risk factors of age, sex, and race/genetics had limited-to-moderate evidence. The tertiary factors of ACE inhibitors and angiotensin II receptor blockers had limited-to-moderate evidence. Ibuprofen and thiazolidinediones had limited evidence.
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Affiliation(s)
- Girish Pathangey
- William Beaumont School of Medicine, Oakland University, Rochester, Michigan
| | | | | | - Amr E Abbas
- William Beaumont School of Medicine, Oakland University, Rochester, Michigan
- Department of Cardiovascular Medicine, Beaumont Hospital Royal Oak, Royal Oak, Michigan
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Suh SH, Ma SK, Kim SW, Bae EH. Angiotensin-converting enzyme 2 and kidney diseases in the era of coronavirus disease 2019. Korean J Intern Med 2021; 36:247-262. [PMID: 33617712 PMCID: PMC7969072 DOI: 10.3904/kjim.2020.355] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 09/19/2020] [Indexed: 01/08/2023] Open
Abstract
In the decades since the discovery of angiotensin-converting enzyme 2 (ACE2), its protective role in terms of antagonizing activation of the classical renin-angiotensin system (RAS) axis has been recognized in clinical and experimental studies on kidney and cardiovascular diseases. The effects of ACE inhibitor/angiotensin type 1 receptor blockers (ACEi/ARBs) on ACE2-angiotensin-(1-7) (Ang- (1-7))-Mas receptor (MasR) axis activation has encouraged the use of such blockers in patients with kidney and cardiovascular diseases, until the emergence of coronavirus disease 2019 (COVID-19). The previously unchallenged functions of the ACE2-Ang-(1-7)-MasR axis and ACEi/ARBs are being re-evaluated in the era of COVID-19; the hypothesis is that ACEi/ARBs may increase the risk of severe acute respiratory syndrome coronavirus 2 infection by upregulating the human ACE2 receptor expression level. In this review, we examine ACE2 molecular structure, function (as an enzyme of the RAS), and distribution. We explore the roles played by ACE2 in kidney, cardiovascular, and pulmonary diseases, highlighting studies that defined the benefits imparted when ACEi/ARBs activated the local ACE2- Ang-(1-7)-MasR axis. Finally, the question of whether ACEi/ARBs therapies should be stopped in COVID-19-infected patients will be reviewed by reference to the available evidence.
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Affiliation(s)
- Sang Heon Suh
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Seong Kwon Ma
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Soo Wan Kim
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Eun Hui Bae
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
- Correspondence to Eun Hui Bae, M.D. Department of Internal Medicine, Chonnam National University Medical School, 42 Jebong-ro, Dong-gu, Gwangju 61469, Korea Tel: +82-62-220-6503 Fax: +82-62-225-8578 E-mail:
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Kuriakose J, Montezano A, Touyz R. ACE2/Ang-(1-7)/Mas1 axis and the vascular system: vasoprotection to COVID-19-associated vascular disease. Clin Sci (Lond) 2021; 135:387-407. [PMID: 33511992 PMCID: PMC7846970 DOI: 10.1042/cs20200480] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 01/07/2021] [Accepted: 01/11/2021] [Indexed: 12/13/2022]
Abstract
The two axes of the renin-angiotensin system include the classical ACE/Ang II/AT1 axis and the counter-regulatory ACE2/Ang-(1-7)/Mas1 axis. ACE2 is a multifunctional monocarboxypeptidase responsible for generating Ang-(1-7) from Ang II. ACE2 is important in the vascular system where it is found in arterial and venous endothelial cells and arterial smooth muscle cells in many vascular beds. Among the best characterized functions of ACE2 is its role in regulating vascular tone. ACE2 through its effector peptide Ang-(1-7) and receptor Mas1 induces vasodilation and attenuates Ang II-induced vasoconstriction. In endothelial cells activation of the ACE2/Ang-(1-7)/Mas1 axis increases production of the vasodilator's nitric oxide and prostacyclin's and in vascular smooth muscle cells it inhibits pro-contractile and pro-inflammatory signaling. Endothelial ACE2 is cleaved by proteases, shed into the circulation and measured as soluble ACE2. Plasma ACE2 activity is increased in cardiovascular disease and may have prognostic significance in disease severity. In addition to its enzymatic function, ACE2 is the receptor for severe acute respiratory syndrome (SARS)-coronavirus (CoV) and SARS-Cov-2, which cause SARS and coronavirus disease-19 (COVID-19) respectively. ACE-2 is thus a double-edged sword: it promotes cardiovascular health while also facilitating the devastations caused by coronaviruses. COVID-19 is associated with cardiovascular disease as a risk factor and as a complication. Mechanisms linking COVID-19 and cardiovascular disease are unclear, but vascular ACE2 may be important. This review focuses on the vascular biology and (patho)physiology of ACE2 in cardiovascular health and disease and briefly discusses the role of vascular ACE2 as a potential mediator of vascular injury in COVID-19.
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Affiliation(s)
- Jithin Kuriakose
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom
| | - Augusto C. Montezano
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom
| | - Rhian M. Touyz
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom
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Marquez A, Wysocki J, Pandit J, Batlle D. An update on ACE2 amplification and its therapeutic potential. Acta Physiol (Oxf) 2021; 231:e13513. [PMID: 32469114 PMCID: PMC7267104 DOI: 10.1111/apha.13513] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 05/20/2020] [Accepted: 05/21/2020] [Indexed: 12/11/2022]
Abstract
The renin angiotensin system (RAS) plays an important role in the pathogenesis of variety of diseases. Targeting the formation and action of angiotensin II (Ang II), the main RAS peptide, has been the key therapeutic target for last three decades. ACE‐related carboxypeptidase (ACE2), a monocarboxypeptidase that had been discovered 20 years ago, is one of the catalytically most potent enzymes known to degrade Ang II to Ang‐(1‐7), a peptide that is increasingly accepted to have organ‐protective properties that oppose and counterbalance those of Ang II. In addition to its role as a RAS enzyme ACE2 is the main receptor for SARS‐CoV‐2. In this review, we discuss various strategies that have been used to achieve amplification of ACE2 activity including the potential therapeutic potential of soluble recombinant ACE2 protein and novel shorter ACE2 variants.
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Affiliation(s)
- Alonso Marquez
- Feinberg Medical SchoolNorthwestern University Chicago IL USA
- Department of Medicine Division of Nephrology and Hypertension Chicago IL USA
| | - Jan Wysocki
- Feinberg Medical SchoolNorthwestern University Chicago IL USA
- Department of Medicine Division of Nephrology and Hypertension Chicago IL USA
| | - Jay Pandit
- Feinberg Medical SchoolNorthwestern University Chicago IL USA
- Department of Medicine Division of Nephrology and Hypertension Chicago IL USA
| | - Daniel Batlle
- Feinberg Medical SchoolNorthwestern University Chicago IL USA
- Department of Medicine Division of Nephrology and Hypertension Chicago IL USA
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ACE2 in the renin-angiotensin system. Clin Sci (Lond) 2020; 134:3063-3078. [PMID: 33264412 DOI: 10.1042/cs20200478] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 11/12/2020] [Accepted: 11/19/2020] [Indexed: 01/01/2023]
Abstract
In 2020 we are celebrating the 20th anniversary of the angiotensin-converting enzyme 2 (ACE2) discovery. This event was a landmark that shaped the way that we see the renin-angiotensin system (RAS) today. ACE2 is an important molecular hub that connects the RAS classical arm, formed mainly by the octapeptide angiotensin II (Ang II) and its receptor AT1, with the RAS alternative or protective arm, formed mainly by the heptapeptides Ang-(1-7) and alamandine, and their receptors, Mas and MrgD, respectively. In this work we reviewed classical and modern literature to describe how ACE2 is a critical component of the protective arm, particularly in the context of the cardiac function, coagulation homeostasis and immune system. We also review recent literature to present a critical view of the role of ACE2 and RAS in the SARS-CoV-2 pandemic.
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ACE2 and ACE: structure-based insights into mechanism, regulation and receptor recognition by SARS-CoV. Clin Sci (Lond) 2020; 134:2851-2871. [PMID: 33146371 PMCID: PMC7642307 DOI: 10.1042/cs20200899] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 10/22/2020] [Accepted: 10/26/2020] [Indexed: 12/21/2022]
Abstract
Angiotensin converting enzyme (ACE) is well-known for its role in blood pressure regulation via the renin–angiotensin aldosterone system (RAAS) but also functions in fertility, immunity, haematopoiesis and diseases such as obesity, fibrosis and Alzheimer’s dementia. Like ACE, the human homologue ACE2 is also involved in blood pressure regulation and cleaves a range of substrates involved in different physiological processes. Importantly, it is the functional receptor for severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 responsible for the 2020, coronavirus infectious disease 2019 (COVID-19) pandemic. Understanding the interaction between SARS-CoV-2 and ACE2 is crucial for the design of therapies to combat this disease. This review provides a comparative analysis of methodologies and findings to describe how structural biology techniques like X-ray crystallography and cryo-electron microscopy have enabled remarkable discoveries into the structure–function relationship of ACE and ACE2. This, in turn, has enabled the development of ACE inhibitors for the treatment of cardiovascular disease and candidate therapies for the treatment of COVID-19. However, despite these advances the function of ACE homologues in non-human organisms is not yet fully understood. ACE homologues have been discovered in the tissues, body fluids and venom of species from diverse lineages and are known to have important functions in fertility, envenoming and insect–host defence mechanisms. We, therefore, further highlight the need for structural insight into insect and venom ACE homologues for the potential development of novel anti-venoms and insecticides.
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Li D, Li B, Peng LX, Liu R, Zeng N. Therapeutic Efficacy of Piperazine Ferulate Combined With Irbesartan in Diabetic Nephropathy: A Systematic Review and Meta-analysis. Clin Ther 2020; 42:2196-2212. [PMID: 33158581 DOI: 10.1016/j.clinthera.2020.09.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 08/05/2020] [Accepted: 09/21/2020] [Indexed: 01/17/2023]
Abstract
PURPOSE Irbesartan is widely used clinically in the treatment of diabetic nephropathy (DN). It is believed that piperazine ferulate (PF) combined with irbesartan could result in an improved efficacy in the treatment of DN. We present the latest meta-analysis that details the combination of PF and irbesartan therapy. METHODS Before January 31, 2020, we searched various electronic databases for appropriate articles. Our search was not restricted by keyword or language. We then filtered all articles using certain criteria and assessed the quality of the qualified studies. FINDINGS The meta-analysis included 12 trials that involved 1300 patients (650 in the experimental group and 650 in the control group). The ages of the patients ranged from 30 to 79 years. Compared with irbesartan alone, the total effective rate of PF combined with irbesartan was significantly higher (odds ratio [OR] = 4.95; 95% CI, 3.11-7.58; P < 0.0001). The blood glucose level was controlled by significantly decreasing the fasting plasma glucose level (mean difference [MD] = -1.40; 95% CI, -2.70 to -0.11; P = 0.03) and 2-h plasma glucose level (MD = -1.65; 95% CI, -2.49 to -0.82; P < 0.0001). The combination therapy significantly decreased the levels of serum creatinine (MD = -10.24; 95% CI, -15.25 to -5.23; P < 0.0001), 24-h urinary protein (MD = -0.07; 95% CI, -0.09 to -0.05; P < 0.0001), urinary albumin excretion rate (MD = -22.52; 95% CI, -30.20 to -14.84; P < 0.0001), urinary β2-microglobulin (MD = -0.15; 95% CI, -0.17 to -0.13; P < 0.0001), and blood urea nitrogen (MD = -1.54; 95% CI, -2.36 to -0.72; P = 0.0002), which was beneficial for improving and protecting renal function. The renal microcirculation was improved by significantly decreasing the whole blood viscosity low shear (MD = -1.41; 95% CI, -1.84 to -0.99; P < 0.0001), whole blood viscosity high shear (MD = -0.54; 95% CI, -0.63 to -0.45; P < 0.0001), whole blood viscosity (MD = -1.31; 95% CI, -1.79 to -0.83; P < 0.0001), whole blood reduction viscosity (MD = -1.42; 95% CI, -1.79 to -1.06; P < 0.0001), platelet aggregation rate (MD = -0.42; 95% CI, -0.50 to -0.35; P < 0.0001), plasma viscosity (MD = -13.02; 95% CI, -15.47 to -10.56; P < 0.0001), and fibrinogen content (MD = -0.25; 95% CI, -0.42 to -0.09; P = 0.003). IMPLICATIONS PF combined with irbesartan could improve the efficiency in the treatment of DN. However, these results should be handled carefully. These findings should be verified by several rigorous randomized controlled trials.
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Affiliation(s)
- Dan Li
- Department of Pharmacology, College of Pharmacy, Chengdu University of TCM, Wenjiang District, Chengdu, Sichuan Province, 611137, PR China
| | - Bo Li
- Chengdu Hanpharm Pharmaceutical Co., Ltd, Pengzhou, Sichuan Province, 611930, PR China
| | - Li-Xia Peng
- Department of Pharmacology, College of Pharmacy, Chengdu University of TCM, Wenjiang District, Chengdu, Sichuan Province, 611137, PR China
| | - Rong Liu
- Department of Pharmacology, College of Pharmacy, Chengdu University of TCM, Wenjiang District, Chengdu, Sichuan Province, 611137, PR China.
| | - Nan Zeng
- Department of Pharmacology, College of Pharmacy, Chengdu University of TCM, Wenjiang District, Chengdu, Sichuan Province, 611137, PR China.
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Sharma N, Gaikwad AB. Ameliorative effect of AT2R and ACE2 activation on ischemic renal injury associated cardiac and hepatic dysfunction. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2020; 80:103501. [PMID: 32979558 DOI: 10.1016/j.etap.2020.103501] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 09/12/2020] [Accepted: 09/17/2020] [Indexed: 06/11/2023]
Abstract
This study explored the role of the depressor arm of renin-angiotensin system (RAS) on ischemic renal injury (IRI)-associated cardio-hepatic sequalae under non-diabetic (ND) and diabetes mellitus (DM) conditions. Firstly, rats were injected with Streptozotocin (55 mg/kg i.p.) to develop DM. ND and DM rats underwent Bilateral IRI followed by 24 h of reperfusion. Further, ND and DM rats were subjected to AT2R agonist-Compound 21 (C21) (0.3 mg/kg/day, i.p.) or ACE2 activator- Diminazene Aceturate (Dize), (5 mg/kg/day, p.o.) per se or its combination therapy. As results, IRI caused cardio-hepatic injuries via altered oxidant/anti-oxidant levels, elevated inflammatory events, and altered protein expressions of ACE, ACE2, Ang II, Ang-(1-7) and urinary AGT. However, concomitant therapy of AT2R agonist and ACE2 activator exerts a protective effect in IRI-associated cardio-hepatic dysfunction as evidenced by inhibited oxidative stress, downregulated inflammation, and enhanced cardio-hepatic depressor arm of RAS under ND and DM conditions.
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Affiliation(s)
- Nisha Sharma
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, 333031, India
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, 333031, India.
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Sharma N, Gaikwad AB. Effects of renal ischemia injury on brain in diabetic and non-diabetic rats: Role of angiotensin II type 2 receptor and angiotensin-converting enzyme 2. Eur J Pharmacol 2020; 882:173241. [PMID: 32565336 DOI: 10.1016/j.ejphar.2020.173241] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 05/28/2020] [Accepted: 05/29/2020] [Indexed: 01/19/2023]
Abstract
Clinically, patients with diabetes mellitus (DM) are more susceptible to ischemic renal injury (IRI) than non-diabetic (ND) patients. Besides, IRI predisposes distant organ dysfunctions including, neurological dysfunction, in which the major contributor remains renin-angiotensin system (RAS). Interestingly, the role of depressor arm of RAS on IRI-associated neurological sequalae remains unclear. Hence, this study aimed to delineate the role of angiotensin II type 2 receptor (AT2R) and angiotensin-converting enzyme 2 (ACE2) under the same. ND and Streptozotocin-induced DM rats with bilateral IRI were treated with AT2R agonist-Compound 21 (C21) (0.3 mg/kg/day, i.p.) or ACE2 activator-Diminazene Aceturate (Dize), (5 mg/kg/day, p.o.) either alone or as combination therapy. Effect of IRI on neurological functions were assessed by behavioural, biochemical, and histopathological analysis. Immunohistochemistry, ELISA and qRT-PCR experiments were conducted for evaluation of the molecular mechanisms. We found that in ND and DM rats, IRI causes increased hippocampal MDA and nitrite levels, augmented inflammatory cytokines (granulocyte-colony stimulating factor, glial fibrillary acidic protein), altered protein levels of Ang II, Ang-(1-7) and mRNA expressions of At1r, At2r and Masr. Treatment with C21 and Dize effectively normalised above-mentioned pathological alterations. Moreover, the protective effect of C21 and Dize combination therapy was better than respective monotherapies, and more likely, exerted via augmentation of protein and mRNA levels of depressor arm components. Thus, AT2R agonist and ACE2 activator therapy prevents the development of IRI-associated neurological dysfunction by attenuating oxidative stress and inflammation, upregulating depressor arm of RAS in brain under ND and DM conditions.
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Affiliation(s)
- Nisha Sharma
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, 333031, India
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, 333031, India.
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Muchtaridi M, Fauzi M, Khairul Ikram NK, Mohd Gazzali A, Wahab HA. Natural Flavonoids as Potential Angiotensin-Converting Enzyme 2 Inhibitors for Anti-SARS-CoV-2. Molecules 2020; 25:E3980. [PMID: 32882868 PMCID: PMC7504743 DOI: 10.3390/molecules25173980] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 08/25/2020] [Accepted: 08/26/2020] [Indexed: 12/21/2022] Open
Abstract
Over the years, coronaviruses (CoV) have posed a severe public health threat, causing an increase in mortality and morbidity rates throughout the world. The recent outbreak of a novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the current Coronavirus Disease 2019 (COVID-19) pandemic that affected more than 215 countries with over 23 million cases and 800,000 deaths as of today. The situation is critical, especially with the absence of specific medicines or vaccines; hence, efforts toward the development of anti-COVID-19 medicines are being intensively undertaken. One of the potential therapeutic targets of anti-COVID-19 drugs is the angiotensin-converting enzyme 2 (ACE2). ACE2 was identified as a key functional receptor for CoV associated with COVID-19. ACE2, which is located on the surface of the host cells, binds effectively to the spike protein of CoV, thus enabling the virus to infect the epithelial cells of the host. Previous studies showed that certain flavonoids exhibit angiotensin-converting enzyme inhibition activity, which plays a crucial role in the regulation of arterial blood pressure. Thus, it is being postulated that these flavonoids might also interact with ACE2. This postulation might be of interest because these compounds also show antiviral activity in vitro. This article summarizes the natural flavonoids with potential efficacy against COVID-19 through ACE2 receptor inhibition.
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Affiliation(s)
- Muchtaridi Muchtaridi
- Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Jl Raya 21.5, Bandung-Sumedang 45363, Indonesia;
| | - M. Fauzi
- Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Jl Raya 21.5, Bandung-Sumedang 45363, Indonesia;
| | - Nur Kusaira Khairul Ikram
- Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Kuala Lumpur 50603, Malaysia;
- Centre for Research in Biotechnology for Agriculture (CEBAR), Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Amirah Mohd Gazzali
- Department of Pharmaceutical Technology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor 11800, Penang, Malaysia;
| | - Habibah A. Wahab
- Pharmaceutical Design and Simulation Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor 11800, Penang, Malaysia
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Ghafouri-Fard S, Noroozi R, Omrani MD, Branicki W, Pośpiech E, Sayad A, Pyrc K, Łabaj PP, Vafaee R, Taheri M, Sanak M. Angiotensin converting enzyme: A review on expression profile and its association with human disorders with special focus on SARS-CoV-2 infection. Vascul Pharmacol 2020; 130:106680. [PMID: 32423553 PMCID: PMC7211701 DOI: 10.1016/j.vph.2020.106680] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 04/24/2020] [Accepted: 05/03/2020] [Indexed: 12/21/2022]
Abstract
Angiotensin-converting enzyme (ACE) and its homologue, ACE2, have been mostly associated with hypertensive disorder. However, recent pandemia of SARS-CoV-2 has put these proteins at the center of attention, as this virus has been shown to exploit ACE2 protein to enter cells. Clear difference in the response of affected patients to this virus has urged researchers to find the molecular basis and pathophysiology of the cell response to this virus. Different levels of expression and function of ACE proteins, underlying disorders, consumption of certain medications and the existence of certain genomic variants within ACE genes are possible explanations for the observed difference in the response of individuals to the SARS-CoV-2 infection. In the current review, we discuss the putative mechanisms for this observation.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Rezvan Noroozi
- Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland
| | - Mir Davood Omrani
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Wojciech Branicki
- Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland
| | - Ewelina Pośpiech
- Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland
| | - Arezou Sayad
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Krzysztof Pyrc
- Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland
| | - Paweł P Łabaj
- Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland
| | - Reza Vafaee
- Proteomics Research Center, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Marek Sanak
- Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland.
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Sankrityayan H, Kale A, Sharma N, Anders HJ, Gaikwad AB. Evidence for Use or Disuse of Renin-Angiotensin System Modulators in Patients Having COVID-19 With an Underlying Cardiorenal Disorder. J Cardiovasc Pharmacol Ther 2020; 25:299-306. [PMID: 32351121 DOI: 10.1177/1074248420921720] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Coronavirus disease 19 (COVID-19) originated in Wuhan, China, in December 2019 has been declared pandemic by World Health Organization due to an exponential rise in the number of infected and deceased persons across the globe. Emerging reports suggest that susceptibility and mortality rates are higher in patients with certain comorbidities when compared to the average population. Cardiovascular diseases and diabetes are important risk factors for a lethal outcome of COVID-19. Extensive research ensuing the outbreak of coronavirus-related severe acute respiratory syndrome in the year 2003, and COVID-19 recently revealed a role of renin-angiotensin system (RAS) components in the entry of coronavirus wherein angiotensin-converting enzyme 2 (ACE2) had garnered the significant attention. This raises the question whether the use of RAS inhibitors, the backbone of treatment of cardiovascular, neurovascular, and kidney diseases could increase the susceptibility for coronavirus infection or unfortunate outcomes of COVID-19. Thus, currently, there is a lack of consensus regarding the effects of RAS inhibitors in such patients. Moreover, expert bodies like American Heart Association, American College of Cardiology, and so on have now released official statements that RAS inhibitors must be continued, unless suggested otherwise by a physician. In this brief review, we will elaborate on the role of RAS and ACE2 in pathogenesis of COVID-19. Moreover, we will discuss the potential effect of the use and disuse of RAS inhibitors in patients having COVID-19 with cardiometabolic comorbidities.
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Affiliation(s)
- Himanshu Sankrityayan
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, Rajasthan, India
| | - Ajinath Kale
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, Rajasthan, India
| | - Nisha Sharma
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, Rajasthan, India
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Internal Medicine IV, University Hospital of the Ludwig Maximilians University Munich, Munich, Germany
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, Rajasthan, India
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Li S, Li Y, Xu H, Wei Z, Yang Y, Jin F, Zhang M, Wang C, Song W, Huo J, Zhao J, Yang X, Yang F. ACE2 Attenuates Epithelial-Mesenchymal Transition in MLE-12 Cells Induced by Silica. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:1547-1559. [PMID: 32368013 PMCID: PMC7183338 DOI: 10.2147/dddt.s252351] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 04/02/2020] [Indexed: 12/19/2022]
Abstract
Purpose The role of angiotensin-converting enzyme 2 (ACE2) in silicosis remains unknown, although previous studies have suggested that ACE2 may be beneficial. We, therefore, investigated the effect of ACE2 on silicosis, particularly with regard to its role in regulating the epithelial-mesenchymal transition (EMT) induced by silica, with the aim to uncover a new potential target for the treatment of pulmonary fibrosis. Materials and Methods We employed wild-type mice treated with diminazene aceturate (DIZE, an ACE2 activator, 15 mg/kg/day for 4 weeks), hACE2-transgenic mice (overexpress the ACE2 gene), and the mouse lung type II epithelial cell line treated with DIZE (10-7 M for 48 h) or angiotensin-(1-7) [Ang-(1-7)] (10-4 M for 48 h), following induced fibrotic responses to determine the protective potential of ACE2. Silicosis models were established by orotracheal instillation of SiO2 (2.5 mg/mouse). Immunostaining was used to determine α-smooth muscle actin (α-SMA) expression. The activities of angiotensin-converting enzyme (ACE) and ACE2 and the levels of angiotensin II (Ang II) and Ang-(1-7) were detected by enzyme-linked immunosorbent assay. The mRNA expression of ACE and ACE2, and protein expression of the renin-angiotensin system (RAS) components and EMT indicators were studied by qRT-PCR and Western blot, respectively. Results DIZE treatment and overexpression of ACE2 markedly inhibited the formation of silica-induced lung fibrosis and increased the level of E-cadherin, with concomitant downregulation of pro-collagen, vimentin, and α-SMA via RAS signaling. Furthermore, DIZE and Ang-(1-7) attenuated the EMT and collagen deposition induced by silica in MLE-12 cells. Moreover, these effects were abrogated by MLN-4760 (a specific ACE2 inhibitor) and A779 (a specific Mas receptor blocker). Conclusion The overexpression of ACE2 and treatment with DIZE can ameliorate EMT in silicotic mice via activation of the ACE2-Ang-(1-7)-Mas receptor axis, and these changes are accompanied by suppression of the ACE-Ang II-AT1 receptor axis.
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Affiliation(s)
- Shumin Li
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei 063210, People's Republic of China.,School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, People's Republic of China
| | - Yaqian Li
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, People's Republic of China.,Hebei Key Laboratory for Organ Fibrosis, North China University of Science and Technology, Tangshan, Hebei 063210, People's Republic of China
| | - Hong Xu
- Hebei Key Laboratory for Organ Fibrosis, North China University of Science and Technology, Tangshan, Hebei 063210, People's Republic of China
| | - Zhongqiu Wei
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, People's Republic of China
| | - Yi Yang
- Academic Affairs Office, North China University of Science and Technology, Tangshan, Hebei 063210, People's Republic of China
| | - Fuyu Jin
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, People's Republic of China.,Hebei Key Laboratory for Organ Fibrosis, North China University of Science and Technology, Tangshan, Hebei 063210, People's Republic of China
| | - Min Zhang
- Hebei Key Laboratory for Organ Fibrosis, North China University of Science and Technology, Tangshan, Hebei 063210, People's Republic of China
| | - Chen Wang
- Hebei Key Laboratory for Organ Fibrosis, North China University of Science and Technology, Tangshan, Hebei 063210, People's Republic of China
| | - Wenxiong Song
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, People's Republic of China
| | - Jingchen Huo
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, People's Republic of China
| | - Jingyuan Zhao
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, People's Republic of China
| | - Xiuhong Yang
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, People's Republic of China
| | - Fang Yang
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei 063210, People's Republic of China.,Hebei Key Laboratory for Organ Fibrosis, North China University of Science and Technology, Tangshan, Hebei 063210, People's Republic of China
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Liu Q, Lv S, Liu J, Liu S, Wang Y, Liu G. Mesenchymal stem cells modified with angiotensin-converting enzyme 2 are superior for amelioration of glomerular fibrosis in diabetic nephropathy. Diabetes Res Clin Pract 2020; 162:108093. [PMID: 32109518 DOI: 10.1016/j.diabres.2020.108093] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 02/14/2020] [Accepted: 02/24/2020] [Indexed: 01/06/2023]
Abstract
AIMS This study aimed to detect the effect of angiotensin-converting enzyme (ACE) 2-modified mesenchymal stem cells (MSCs) on glomerular fibrosis in vitro and in vivo and investigate the underlying molecular mechanism. METHODS MSCs transduced with the ACE2 gene (MSCs-ACE2) were cocultured with glomerular mesangial cells (GMCs) following Ang II stimulation. MSCs-ACE2 were transplanted into streptozotocin-induced diabetic rats. Physical, biochemical and morphological parameters were measured, and fibrotic indicators and renin-angiotensin system (RAS) components in GMCs and kidney tissues were assessed. RESULTS The transduction efficiency of MSCs was as high as 85%. The modified MSCs secreted soluble ACE2 protein into the culture medium. After transplantation into rats with diabetes, MSCs-ACE2 targeted injured kidneys and enhanced local expression of ACE2. Compared with MSC treatment alone, MSC-ACE2 treatment was superior in reducing albuminuria and improving glomerulosclerosis. In vitro and in vivo, MSCs-ACE2 were more beneficial than MSCs alone in decreasing Ang II and increasing Ang1-7, thereby inhibiting the detrimental effects of Ang II accumulation by downregulating collagen I and fibronectin (FN) expression and inhibiting the transforming growth factor (TGF-β)/Smad pathway. CONCLUSIONS MSCs modified with ACE2 therapy have additional benefits to the progression of diabetic nephropathy (DN) by inhibiting renal RAS activation and reducing glomerular fibrosis.
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Affiliation(s)
- Qingzhen Liu
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China
| | - Shasha Lv
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China
| | - Jiaxi Liu
- College of Liberal Arts, University of Minnesota, USA
| | - Shanshan Liu
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China
| | - Yinghui Wang
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China
| | - Gang Liu
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China.
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Malek V, Gaikwad AB. Telmisartan and thiorphan combination treatment attenuates fibrosis and apoptosis in preventing diabetic cardiomyopathy. Cardiovasc Res 2020; 115:373-384. [PMID: 30184174 DOI: 10.1093/cvr/cvy226] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 08/28/2018] [Indexed: 01/02/2023] Open
Abstract
Aims LCZ696, a first-generation dual angiotensin receptor-neprilysin inhibitor (ARNi), is effective in treating heart failure patients. However, the role of ARNis in treating diabetic cardiomyopathy is poorly understood. This study evaluates the efficacy of a novel combination of telmisartan [angiotensin receptor blocker (ARB)] and thiorphan [neprilysin inhibitor (NEPi)] in ameliorating diabetic cardiomyopathy while, at the same time, exploring the relevant underlying molecular mechanism(s). Methods and results Diabetes was induced by administration of streptozotocin (55 mg/kg, i.p.) in male Wistar rats. After 4 weeks, diabetic rats were subjected to either thiorphan (0.1 mg/kg/day, p.o.) or telmisartan (10 mg/kg/day, p.o.) monotherapy, or their combination, for a period of 4 weeks. Metabolic and morphometric alterations, failing ventricular functions, and diminished baroreflex indicated development of diabetic cardiac complications. Apart from morphometric alterations, all pathological consequences were prevented by telmisartan and thiorphan combination therapy. Diabetic rats exhibited significant modulation of the natriuretic peptide system, a key haemodynamic regulator; this was normalized by combination therapy. Histopathological studies showed augmented myocardial fibrosis, demonstrated by increased % PSR-positive area, with combination therapy giving the best improvement in these indices. More importantly, the combination of thiorphan and telmisartan was superior in attenuating inflammatory (NF-κB/MCP-1), profibrotic (TGF-β/Smad7) and apoptotic (PARP/Caspase-3) cascades compared to respective monotherapies when treating rats with diabetic cardiomyopathy. In addition, diabetic heart chromatin was in a state of active transcription, indicated by increased histone acetylation (H2AK5Ac, H2BK5Ac, H3K9Ac, and H4K8Ac) and histone acetyltransferase (PCAF and Ac-CBP) levels. Interestingly, combination treatment was sufficiently potent to normalize these alterations. Conclusion The protective effect of novel ARB and NEPi combination against diabetic cardiomyopathy can be attributed to inhibition of inflammatory, profibrotic, and apoptotic cascades. Moreover, reversal of histone acetylation assists its protective effect.
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Affiliation(s)
- Vajir Malek
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, India
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, India
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