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Akunjee MM, Khosla SG, Nylen ES, Sen S. SGLT2 inhibitors use in kidney disease: what did we learn? Am J Physiol Endocrinol Metab 2025; 328:E856-E868. [PMID: 40279256 DOI: 10.1152/ajpendo.00034.2025] [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: 02/27/2025] [Revised: 03/26/2025] [Accepted: 04/18/2025] [Indexed: 04/27/2025]
Abstract
Chronic kidney disease (CKD) increases the risk for cardiovascular morbidity and mortality and it's prevalence continues to rise throughout the world. Newer, more efficacious therapies, slow progression of CKD, decrease long-term sequela like end-stage kidney disease (ESKD) and cardiovascular events, improving survival. Postmarketing cardiovascular outcome trials (CVOT) have demonstrated improved cardiovascular outcomes with the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) like canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin in patients with type 2 diabetes mellitus (T2DM), Similarly, secondary analysis of CVOT and renal outcome trials with the use of SGLT2i in patients without T2DM showed improved renal function and albuminuria. In these studies, nondiabetic CKD was defined as an estimated glomerular filtration rate (eGFR) of 20-75 mL/min/1.73 m2 with albuminuria ranging from 200 to 5,000 mg/g in the absence of diabetes. As a class effect, in addition to modulation of hemodynamic and metabolic activities, SGLT2i exert renal protection by suppressing inflammation and fibrosis. We conducted an extensive search in the PubMed database for original papers published from 2009 through 2024 using keywords such as nondiabetic kidney disease, diabetic kidney disease, SGLT2i, and kidney outcomes. Based on our research of published literature, we present a review and propose, consideration of SGLT2i in nondiabetic kidney disease for long-term cardiovascular and renal benefit (Dharia A, Khan A, Sridhar VS, Cherney DZI. Annu Rev Med 74: 369-384, 2023). We will highlight relevant translational studies to propose a possible cell-based mechanism for cardiovascular benefits noted secondary to use of SGLT2i.
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Affiliation(s)
- Munaza M Akunjee
- Division of Endocrinology, Department of Medicine, Veterans Affairs Medical Center, Washington, District of Columbia, United States
- Division of Endocrinology, Department of Medicine, The George Washington University, Washington, District of Columbia, United States
| | - Shikha G Khosla
- Division of Endocrinology, Department of Medicine, Veterans Affairs Medical Center, Washington, District of Columbia, United States
- Division of Endocrinology, Department of Medicine, The George Washington University, Washington, District of Columbia, United States
| | - Eric S Nylen
- Division of Endocrinology, Department of Medicine, Veterans Affairs Medical Center, Washington, District of Columbia, United States
- Division of Endocrinology, Department of Medicine, The George Washington University, Washington, District of Columbia, United States
| | - Sabyasachi Sen
- Division of Endocrinology, Department of Medicine, Veterans Affairs Medical Center, Washington, District of Columbia, United States
- Division of Endocrinology, Department of Medicine, The George Washington University, Washington, District of Columbia, United States
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Patel TA, Zheng H, Patel KP. Sodium-Glucose Cotransporter 2 Inhibitors as Potential Antioxidant Therapeutic Agents in Cardiovascular and Renal Diseases. Antioxidants (Basel) 2025; 14:336. [PMID: 40227417 PMCID: PMC11939188 DOI: 10.3390/antiox14030336] [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: 02/25/2025] [Revised: 03/10/2025] [Accepted: 03/12/2025] [Indexed: 04/15/2025] Open
Abstract
Redox (reduction-oxidation) imbalance is a physiological feature regulated by a well-maintained equilibrium between reactive oxygen species (ROS) and oxidative stress (OS), the defense system of the body (antioxidant enzymes). The redox system comprises regulated levels of ROS in the cells, tissues and the overall organ system. The levels of ROS are synchronized by gradients of electrons that are generated due to sequential reduction and oxidation of various biomolecules by various enzymes. Such redox reactions are present in each cell, irrespective of any tissue or organ. Failure in such coordinated regulation of redox reactions leads to the production of excessive ROS and free radicals. Excessively produced free radicals and oxidative stress affect various cellular and molecular processes required for cell survival and growth, leading to pathophysiological conditions and, ultimately, organ failure. Overproduction of free radicals and oxidative stress are the key factors involved in the onset and progression of pathophysiological conditions associated with various cardiovascular and renal diseases. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are glucose-lowering drugs prescribed to diabetic patients. Interestingly, apart from their glucose-lowering effect, these drugs exhibit beneficial effects in non-diabetic patients suffering from various cardiovascular and chronic kidney diseases, perhaps due to their antioxidant properties. Recently, it has been demonstrated that SGLT2is exhibit strong antioxidant properties by reducing ROS and OS. Hence, in this review, we aim to present the novel antioxidant role of SGLT2is and their consequent beneficial effects in various cardiovascular and renal disease states.
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Affiliation(s)
- Tapan A. Patel
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center (UNMC), Omaha, NE 68198, USA;
| | - Hong Zheng
- Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD 57069, USA
| | - Kaushik P. Patel
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center (UNMC), Omaha, NE 68198, USA;
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Prasad MK, Victor PS, Ganesh GV, Juttada U, Kumpatla S, Viswanathan V, Ramkumar KM. Sodium-Glucose Cotransporter-2 Inhibitor Suppresses Endoplasmic Reticulum Stress and Oxidative Stress in Diabetic Nephropathy Through Nrf2 Signaling: A Clinical and Experimental Study. J Clin Pharmacol 2024; 64:1193-1203. [PMID: 38831713 DOI: 10.1002/jcph.2465] [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: 03/17/2024] [Accepted: 05/08/2024] [Indexed: 06/05/2024]
Abstract
Diabetic nephropathy (DN), a severe complication of type 2 diabetes mellitus (T2DM), is marked by heightened endoplasmic reticulum stress (ERS) and oxidative stress (OS) due to protein misfolding and free radical generation. We investigated the sodium-glucose co-transporter-2 inhibitor (SGLT2i), canagliflozin (Cana), in alleviating ERS and OS in DN patients and THP-1 cells under hyperglycemic condition. A total of 120 subjects were divided into four groups, with 30 subjects in each group: healthy controls, T2DM individuals, DN patients receiving standard treatment, and those treated with Cana. The control group had no history of diabetes, cardiovascular or renal diseases, or other comorbidities. Cana was administered at doses of either 100 or 300 mg per day based on the estimated glomerular filtration rate (eGFR) value of DN individuals, with a mean follow-up of 6 months. Additionally, THP-1 monocytes were exposed to HGM (33.3 mM glucose with a cytokine cocktail of TNF-α and IFN-γ at 50 ng/mL each) to evaluate the relative levels of ERS, OS markers, and nuclear factor erythroid 2-related factor 2 (Nrf2), the transcription factor regulating cellular redox, which is downregulated in diabetes. Our results revealed that ERS markers GRP78 and PERK, as well as OS markers TXNIP and p22phox, were elevated in both DN patients and HGM-treated THP-1 monocytes and were reduced by Cana intervention. Furthermore, Cana regulated the phosphorylation of Nrf2, Akt, and EIF2α in HGM-treated monocytes. In conclusion, our findings highlight the role of Cana in activating Nrf2, thereby attenuating ERS and OS to mitigate DN progression.
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Affiliation(s)
- Murali Krishna Prasad
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamilnadu, India
| | - Paul S Victor
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamilnadu, India
| | - Goutham V Ganesh
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamilnadu, India
| | - Udayama Juttada
- Department of Biochemistry and Molecular Genetics, Prof. M. Viswanathan's Diabetes Research Center, M.V. Hospital for Diabetes, Royapuram Chennai, Tamilnadu, India
| | - Satyavani Kumpatla
- Department of Biochemistry and Molecular Genetics, Prof. M. Viswanathan's Diabetes Research Center, M.V. Hospital for Diabetes, Royapuram Chennai, Tamilnadu, India
| | - Vijay Viswanathan
- Department of Biochemistry and Molecular Genetics, Prof. M. Viswanathan's Diabetes Research Center, M.V. Hospital for Diabetes, Royapuram Chennai, Tamilnadu, India
| | - Kunka Mohanram Ramkumar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamilnadu, India
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Forouzanmehr B, Hedayati AH, Gholami E, Hemmati MA, Maleki M, Butler AE, Jamialahmadi T, Kesharwani P, Yaribeygi H, Sahebkar A. Sodium-glucose cotransporter 2 inhibitors and renin-angiotensin-aldosterone system, possible cellular interactions and benefits. Cell Signal 2024; 122:111335. [PMID: 39117253 DOI: 10.1016/j.cellsig.2024.111335] [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: 06/23/2024] [Revised: 07/30/2024] [Accepted: 08/04/2024] [Indexed: 08/10/2024]
Abstract
Sodium glucose cotransporter 2 inhibitors (SGLT2is) are a newly developed class of anti-diabetics which exert potent hypoglycemic effects in the diabetic milieu. However, the evidence suggests that they also have extra-glycemic effects. The renin-angiotensin-aldosterone system (RAAS) is a hormonal system widely distributed in the body that is important for water and electrolyte homeostasis as well as renal and cardiovascular function. Therefore, modulating RAAS activity is a main goal in patients, notably diabetic patients, which are at higher risk of complications involving these organ systems. Some studies have suggested that SGLT2is have modulatory effects on RAAS activity in addition to their hypoglycemic effects and, thus, these drugs can be considered as promising therapeutic agents for renal and cardiovascular disorders. However, the exact molecular interactions between SGLT2 inhibition and RAAS activity are not clearly understood. Therefore, in the current study we surveyed the literature for possible molecular mechanisms by which SGLT2is modulate RAAS activity.
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Affiliation(s)
- Behina Forouzanmehr
- Student Research Committee, Semnan University of Medical Sciences, Semnan, Iran
| | | | - Emad Gholami
- Student Research Committee, Semnan University of Medical Sciences, Semnan, Iran
| | | | - Mina Maleki
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alexandra E Butler
- Research Department, Royal College of Surgeons in Ireland Bahrain, Adliya 15503, Bahrain
| | - Tannaz Jamialahmadi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
| | - Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran.
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
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Wagner BR, Rao PS. Sodium-glucose cotransporter 2 inhibitors: are they ready for prime time in the management of lupus nephritis? Curr Opin Rheumatol 2024; 36:163-168. [PMID: 38517337 DOI: 10.1097/bor.0000000000001002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2024]
Abstract
PURPOSE OF REVIEW Lupus nephritis is a common complication of systemic lupus erythematosus and is associated with significant morbidity and mortality. The utility of sodium-glucose cotransporter 2 (SGLT2) inhibitors in the management of lupus nephritis is currently uncertain. Here, we summarize the rationale for their use among patient with lupus nephritis. RECENT FINDINGS SGLT2 inhibitors were initially developed as antihyperglycemic agents. They have since been shown to have additional, profound effects to slow the progression of chronic kidney disease and lessen the long-term risks of cardiovascular disease in large clinic trials of patients with chronic kidney disease, with and without diabetes, as well as in patients with and without proteinuria. Patients with recent exposure to immunosuppression were excluded from these trials due to concern for risk of infection. In the few, small trials of patients with lupus nephritis, SGLT2 inhibitors were found to be well tolerated. They have been shown to reduce proteinuria and to have modest beneficial effects on blood pressure and BMI among patients with lupus nephritis. They have not been shown to influence disease activity. SUMMARY SGLT2 inhibitors may have a role in mitigating the chronic renal and cardiovascular effects of lupus nephritis. They should be introduced after kidney function has been stabilized with appropriate immunosuppression, in conjunction with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. They currently have no role in active disease.
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Affiliation(s)
- Benjamin R Wagner
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
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Song J, Zhang B, Zhang H, Cheng W, Liu P, Kang J. Quantitative Proteomics Combined with Network Pharmacology Analysis Unveils the Biological Basis of Schisandrin B in Treating Diabetic Nephropathy. Comb Chem High Throughput Screen 2024; 27:284-297. [PMID: 37151069 DOI: 10.2174/1386207326666230505111903] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 03/16/2023] [Accepted: 03/22/2023] [Indexed: 05/09/2023]
Abstract
BACKGROUND Diabetic nephropathy (DN) is a major complication of diabetes. Schisandrin B (Sch) is a natural pharmaceutical monomer that was shown to prevent kidney damage caused by diabetes and restore its function. However, there is still a lack of comprehensive and systematic understanding of the mechanism of Sch treatment in DN. OBJECTIVE We aim to provide a systematic overview of the mechanisms of Sch in multiple pathways to treat DN in rats. METHODS Streptozocin was used to build a DN rat model, which was further treated with Sch. The possible mechanism of Sch protective effects against DN was predicted using network pharmacology and was verified by quantitative proteomics analysis. RESULTS High dose Sch treatment significantly downregulated fasting blood glucose, creatinine, blood urea nitrogen, and urinary protein levels and reduced collagen deposition in the glomeruli and tubule-interstitium of DN rats. The activities of superoxide dismutase (SOD) and plasma glutathione peroxidase (GSH-Px) in the kidney of DN rats significantly increased with Sch treatment. In addition, the levels of IL-6, IL-1β, and TNF-α were significantly reduced in DN rats treated with Sch. 11 proteins that target both Sch and DN were enriched in pathways such as MAPK signaling, PI3K-Akt signaling, renal cell carcinoma, gap junction, endocrine resistance, and TNF signaling. Furthermore, quantitative proteomics showed that Xaf1 was downregulated in the model vs. control group and upregulated in the Sch-treated vs. model group. Five proteins, Crb3, Tspan4, Wdr45, Zfp512, and Tmigd1, were found to be upregulated in the model vs. control group and downregulated in the Sch vs. model group. Three intersected proteins between the network pharmacology prediction and proteomics results, Crb3, Xaf1, and Tspan4, were identified. CONCLUSION Sch functions by relieving oxidative stress and the inflammatory response by regulating Crb3, Xaf1, and Tspan4 protein expression levels to treat DN disease.
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Affiliation(s)
- Jianying Song
- School of Life Sciences, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, People's Republic of China
| | - Bo Zhang
- Institute for TCM-X, MOE Key Laboratory of Bioinformatics, Bioinformatics Division, BNRist, Department of Automation, Tsinghua University, Beijing, 100084, China
| | - Huiping Zhang
- Shanghai Applied Protein Technology Co., Ltd., 58 Yuanmei Road, Shanghai, 200233, People's Republic of China
| | - Wenbo Cheng
- Tianjin Key Laboratory of Medical Mass Spectrometry for Accurate Diagnosis, Tianjin, 300399, People's Republic of China
| | - Peiyuan Liu
- School of Life Sciences, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, People's Republic of China
| | - Jun Kang
- School of Life Sciences, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, People's Republic of China
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Denimal D. Antioxidant and Anti-Inflammatory Functions of High-Density Lipoprotein in Type 1 and Type 2 Diabetes. Antioxidants (Basel) 2023; 13:57. [PMID: 38247481 PMCID: PMC10812436 DOI: 10.3390/antiox13010057] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 12/24/2023] [Accepted: 12/27/2023] [Indexed: 01/23/2024] Open
Abstract
(1) Background: high-density lipoproteins (HDLs) exhibit antioxidant and anti-inflammatory properties that play an important role in preventing the development of atherosclerotic lesions and possibly also diabetes. In turn, both type 1 diabetes (T1D) and type 2 diabetes (T2D) are susceptible to having deleterious effects on these HDL functions. The objectives of the present review are to expound upon the antioxidant and anti-inflammatory functions of HDLs in both diabetes in the setting of atherosclerotic cardiovascular diseases and discuss the contributions of these HDL functions to the onset of diabetes. (2) Methods: this narrative review is based on the literature available from the PubMed database. (3) Results: several antioxidant functions of HDLs, such as paraoxonase-1 activity, are compromised in T2D, thereby facilitating the pro-atherogenic effects of oxidized low-density lipoproteins. In addition, HDLs exhibit diminished ability to inhibit pro-inflammatory pathways in the vessels of individuals with T2D. Although the literature is less extensive, recent evidence suggests defective antiatherogenic properties of HDL particles in T1D. Lastly, substantial evidence indicates that HDLs play a role in the onset of diabetes by modulating glucose metabolism. (4) Conclusions and perspectives: impaired HDL antioxidant and anti-inflammatory functions present intriguing targets for mitigating cardiovascular risk in individuals with diabetes. Further investigations are needed to clarify the influence of glycaemic control and nephropathy on HDL functionality in patients with T1D. Furthermore, exploring the effects on HDL functionality of novel antidiabetic drugs used in the management of T2D may provide intriguing insights for future research.
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Affiliation(s)
- Damien Denimal
- Unit 1231, Center for Translational and Molecular Medicine, University of Burgundy, 21000 Dijon, France;
- Department of Clinical Biochemistry, Dijon Bourgogne University Hospital, 21079 Dijon, France
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Niknejad A, Hosseini Y, Shamsnia HS, Kashani AS, Rostamian F, Momtaz S, Abdolghaffari AH. Sodium Glucose Transporter-2 Inhibitors (SGLT2Is)-TLRs Axis Modulates Diabetes. Cell Biochem Biophys 2023; 81:599-613. [PMID: 37658280 DOI: 10.1007/s12013-023-01164-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/06/2023] [Indexed: 09/03/2023]
Abstract
Diabetes affects millions of people worldwide and is mainly associated with impaired insulin function. To date, various oral anti-diabetic drugs have been developed, of which, the sodium glucose transporter-2 inhibitors (SGLT2Is) are of the most recent classes that have been introduced. They differ from other classes in terms of their novel mechanism of actions and unique beneficial effects rather than just lowering glucose levels. SGLT2Is can protect body against cardiovascular events and kidney diseases even in non-diabetic individuals. SGLT2Is participate in immune cell activation, oxidative stress reduction, and inflammation mediation, thereby, moderating diabetic complications. In addition, toll like receptors (TLRs) are the intermediators of the immune system and inflammatory process, thus it's believed to play crucial roles in diabetic complications, particularly the ones that are related to inflammatory reactions. SGLT2Is are also effective against diabetic complications via their anti-inflammatory and oxidative properties. Given the anti-inflammatory properties of TLRs and SGLT2Is, this review investigates how SGLT2Is can affect the TLR pathway, and whether this could be favorable toward diabetes.
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Affiliation(s)
- Amirhossein Niknejad
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Yasamin Hosseini
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Hedieh Sadat Shamsnia
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Ayeh Sabbagh Kashani
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Fatemeh Rostamian
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Saeideh Momtaz
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran.
- Department of Toxicology and Pharmacology, School of Pharmacy, and Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.
| | - Amir Hossein Abdolghaffari
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
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Dai ZC, Chen JX, Zou R, Liang XB, Tang JX, Yao CW. Role and mechanisms of SGLT-2 inhibitors in the treatment of diabetic kidney disease. Front Immunol 2023; 14:1213473. [PMID: 37809091 PMCID: PMC10552262 DOI: 10.3389/fimmu.2023.1213473] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 09/06/2023] [Indexed: 10/10/2023] Open
Abstract
Diabetic kidney disease (DKD) is a chronic inflammatory condition that affects approximately 20-40% of individuals with diabetes. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors, emerging as novel hypoglycemic agents, have demonstrated significant cardiorenal protective effects in patients with DKD. Initially, it was believed that the efficacy of SGLT-2 inhibitors declined as the estimated glomerular filtration rate (eGFR) decreased, which led to their preferential use in DKD patients at G1-G3 stages. However, recent findings from the DAPA-CKD and EMPA-KIDNEY studies have revealed equally beneficial cardiorenal effects of SGLT-2 inhibitors in individuals at stage G4 DKD, although the underlying mechanism behind this phenomenon remains unclear. In this comprehensive analysis, we provide a systematic review of the mechanisms and functioning of SGLT-2 inhibitors, potential renal protection mechanisms, and the therapeutic efficacy and safety of SGLT-2 inhibitors in kidney diseases, with a particular focus on stage G4 DKD. Gaining a deeper understanding of the renal protective effect of SGLT-2 inhibitors and their underlying mechanisms is highly significance for the successful utilization of these inhibitors in the treatment of diverse kidney disorders.
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Affiliation(s)
| | | | | | | | - Ji-Xin Tang
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Diseases of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Cui-Wei Yao
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Diseases of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
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Ashfaq A, Meineck M, Pautz A, Arioglu-Inan E, Weinmann-Menke J, Michel MC. A systematic review on renal effects of SGLT2 inhibitors in rodent models of diabetic nephropathy. Pharmacol Ther 2023; 249:108503. [PMID: 37495021 DOI: 10.1016/j.pharmthera.2023.108503] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 07/19/2023] [Accepted: 07/20/2023] [Indexed: 07/28/2023]
Abstract
We have performed a systematic review of studies reporting on the renal effects of SGLT2 inhibitors in rodent models of diabetes. In 105 studies, SGLT2 inhibitors improved not only the glycemic control but also various aspects of renal function in most cases. These nephroprotective effects were similarly reported whether treatment with the SGLT2 inhibitor started concomitant with the onset of diabetes (within 1 week), early after onset (1-4 weeks) or after nephropathy had developed (>4 weeks after onset) with the latter probably having the greatest translational value. They were observed across various animal models of type 1 and type 2 diabetes/obesity (4 and 23 models, respectively), although studies in the type 2 diabetes model of db/db mice more often had negative data than in other models. Among possibly underlying pathophysiological mechanisms of nephroprotection, treatment with SGLT2 inhibitors had beneficial effects on lipid metabolism, blood pressure, glomerulosclerosis as well as renal tubular fibrosis, apoptosis, oxidative stress, and inflammation. These pathomechanisms highly influence atherosclerosis and renal health, which are two major factors that lead to an enhanced mortality in patients with diabetes and/or chronic kidney disease. Interestingly, renal SGLT2 inhibitor effects did not always correlate with those on glucose homeostasis, particularly in a limited number of direct comparative studies with other anti-diabetic treatments, indicating that nephroprotection may at least partly occur by mechanisms other than improving glycemic control. Our analyses did not provide evidence for different nephroprotective efficacy between SGLT2 inhibitors. Importantly, only four of 105 studies reported on female animals, and none provided direct comparative data between sexes. We conclude that more data on female animals and more direct comparative studies with other anti-diabetic compounds and combinations of treatments are needed.
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Affiliation(s)
- Aqsa Ashfaq
- Dept. of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany
| | - Myriam Meineck
- 1(st) Dept. of Medicine, Div. of Nephrology, University Medical Center, Johannes Gutenberg University, Mainz, Germany
| | - Andrea Pautz
- Dept. of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany
| | - Ebru Arioglu-Inan
- Dept. of Pharmacology, Faculty of Pharmacy, Ankara University, Ankara, Turkey
| | - Julia Weinmann-Menke
- 1(st) Dept. of Medicine, Div. of Nephrology, University Medical Center, Johannes Gutenberg University, Mainz, Germany
| | - Martin C Michel
- Dept. of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
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Klen J, Dolžan V. SGLT2 Inhibitors in the Treatment of Diabetic Kidney Disease: More than Just Glucose Regulation. Pharmaceutics 2023; 15:1995. [PMID: 37514181 PMCID: PMC10386344 DOI: 10.3390/pharmaceutics15071995] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 06/30/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Diabetic kidney disease (DKD) is a severe and common complication and affects a quarter of patients with type 2 diabetes mellitus (T2DM). Oxidative stress and inflammation related to hyperglycemia are interlinked and contribute to the occurrence of DKD. It was shown that sodium-glucose cotransporter-2 (SGLT2) inhibitors, a novel yet already widely used therapy, may prevent the development of DKD and alter its natural progression. SGLT2 inhibitors induce systemic and glomerular hemodynamic changes, provide metabolic advantages, and reduce inflammatory and oxidative stress pathways. In T2DM patients, regardless of cardiovascular diseases, SGLT2 inhibitors may reduce albuminuria, progression of DKD, and doubling of serum creatinine levels, thus lowering the need for kidney replacement therapy by over 40%. The molecular mechanisms behind these beneficial effects of SGLT2 inhibitors extend beyond their glucose-lowering effects. The emerging studies are trying to explain these mechanisms at the genetic, epigenetic, transcriptomic, and proteomic levels.
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Affiliation(s)
- Jasna Klen
- Division of Surgery, Department of Abdominal Surgery, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
- Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Vita Dolžan
- Pharmacogenetics Laboratory, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
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12
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Piccirillo F, Mastroberardino S, Nusca A, Frau L, Guarino L, Napoli N, Ussia GP, Grigioni F. Novel Antidiabetic Agents and Their Effects on Lipid Profile: A Single Shot for Several Cardiovascular Targets. Int J Mol Sci 2023; 24:10164. [PMID: 37373310 PMCID: PMC10299555 DOI: 10.3390/ijms241210164] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 06/06/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Type-2 diabetes mellitus (DM) represents one of the most important risk factors for cardiovascular diseases (CVD). Hyperglycemia and glycemic variability are not the only determinant of the increased cardiovascular (CV) risk in diabetic patients, as a frequent metabolic disorder associated with DM is dyslipidemia, characterized by hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol levels and a shift towards small dense low-density lipoprotein (LDL) cholesterol. This pathological alteration, also called diabetic dyslipidemia, represents a relevant factor which could promotes atherosclerosis and subsequently an increased CV morbidity and mortality. Recently, the introduction of novel antidiabetic agents, such as sodium glucose transporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i) and glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs), has been associated with a significant improvement in CV outcomes. Beyond their known action on glycemia, their positive effects on the CV system also seems to be related to an ameliorated lipidic profile. In this context, this narrative review summarizes the current knowledge regarding these novel anti-diabetic drugs and their effects on diabetic dyslipidemia, which could explain the provided global benefit to the cardiovascular system.
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Affiliation(s)
- Francesco Piccirillo
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Sara Mastroberardino
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Annunziata Nusca
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Lorenzo Frau
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Lorenzo Guarino
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Nicola Napoli
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Endocrinology and Diabetes Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Gian Paolo Ussia
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Francesco Grigioni
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
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13
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Yu H, Song YY, Li XH. Early diabetic kidney disease: Focus on the glycocalyx. World J Diabetes 2023; 14:460-480. [PMID: 37273258 PMCID: PMC10236994 DOI: 10.4239/wjd.v14.i5.460] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 03/10/2023] [Accepted: 04/12/2023] [Indexed: 05/15/2023] Open
Abstract
The incidence of diabetic kidney disease (DKD) is sharply increasing worldwide. Microalbuminuria is the primary clinical marker used to identify DKD, and its initiating step in diabetes is glomerular endothelial cell dysfunction, particularly glycocalyx impairment. The glycocalyx found on the surface of glomerular endothelial cells, is a dynamic hydrated layer structure composed of pro-teoglycans, glycoproteins, and some adsorbed soluble components. It reinforces the negative charge barrier, transduces the shear stress, and mediates the interaction of blood corpuscles and podocytes with endothelial cells. In the high-glucose environment of diabetes, excessive reactive oxygen species and proinflammatory cytokines can damage the endothelial glycocalyx (EG) both directly and indirectly, which induces the production of microalbuminuria. Further research is required to elucidate the role of the podocyte glycocalyx, which may, together with endothelial cells, form a line of defense against albumin filtration. Interestingly, recent research has confirmed that the negative charge barrier function of the glycocalyx found in the glomerular basement membrane and its repulsion effect on albumin is limited. Therefore, to improve the early diagnosis and treatment of DKD, the potential mechanisms of EG degradation must be analyzed and more responsive and controllable targets must be explored. The content of this review will provide insights for future research.
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Affiliation(s)
- Hui Yu
- Department of Nephrology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Yi-Yun Song
- Department of Nephrology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Xian-Hua Li
- Department of Nephrology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
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14
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Peng X, Zhang HP. Acute Cardiorenal Syndrome: Epidemiology, Pathophysiology, Assessment, and Treatment. Rev Cardiovasc Med 2023; 24:40. [PMID: 39077395 PMCID: PMC11273150 DOI: 10.31083/j.rcm2402040] [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: 10/01/2022] [Revised: 12/05/2022] [Accepted: 12/06/2022] [Indexed: 07/31/2024] Open
Abstract
Acute cardiorenal syndrome (CRS) is often observed in patients with acute kidney injury (AKI) in the cardiac intensive care unit and is reported to be associated with poor prognosis. Volume disorder or re-distribution, renin-angiotensin-aldosterone system activation, and neurohormonal and sympathetic nervous system activation have been suggested to be related to the occurrence of acute CRS. There is a lack of biomarkers that can identify changes in renal function in patients with acute CRS. Evidence-based medications are limited in the management of acute CRS in AKI. Therefore, we reviewed the epidemiology, pathophysiology, clinical assessment, and treatment of acute CRS in AKI.
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Affiliation(s)
- Xi Peng
- Department of Cardiology, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730 Beijing, China
| | - Hui-Ping Zhang
- Department of Cardiology, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730 Beijing, China
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15
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Abstract
Sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) were originally developed as antidiabetic agents, with cardiovascular (CV) outcome trials demonstrating improved CV outcomes in patients with type 2 diabetes mellitus (T2D). Secondary analyses of CV outcome trials and later dedicated kidney outcome trials consistently reported improved kidney-related outcomes independent of T2D status and across a range of kidney function and albuminuria. Importantly, SGLT2 inhibitors are generally safe and well tolerated, with clinical trials and real-world analyses demonstrating a decrease in the risk of acute kidney injury. The kidney protective effects of SGLT2 inhibitors generally extend across different members of the class, possibly on the basis of hemodynamic, metabolic, anti-inflammatory, and antifibrotic mechanisms. In this review, we summarize the effects of SGLT2 inhibitors on kidney outcomes in diverse patient populations.
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Affiliation(s)
- Atit Dharia
- Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada; , , , .,Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Abid Khan
- Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada; , , , .,Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Vikas S Sridhar
- Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada; , , , .,Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - David Z I Cherney
- Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada; , , , .,Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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16
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Toll-like receptors 2 and 4 stress signaling and sodium-glucose cotransporter-2 in kidney disease. Mol Cell Biochem 2022:10.1007/s11010-022-04652-5. [PMID: 36586092 DOI: 10.1007/s11010-022-04652-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 12/23/2022] [Indexed: 01/01/2023]
Abstract
Kidney disease is the 6th fastest-growing cause of death and a serious global health concern that urges effective therapeutic options. The inflammatory response is an initial reaction from immune and parenchymal cells in kidney diseases. Toll-like receptors (TLR) 2 and 4 are highly expressed by various kidney cells and respond to 'signaling danger' proteins, such as high mobility group box binding protein 1 (HMGB1) and prompt the progression of kidney disease by releasing inflammatory mediators. Burgeoning reports suggest that both SGLT2 and ER stress elevates TLR2/4 signaling via different axis. Moreover, SGLT2 signaling aggravates inflammation under the disease condition by promoting the NLR family pyrin domain-containing three inflammasomes and ER stress. Intriguingly, TLR2/4 downstream adaptors activate ER stress regulators. The above-discussed interactions imply that TLR2/4 does more than immune response during kidney disease. Here, we discuss in detail evidence of the roles and regulation of TLR2/4 in the context of a relationship between ER stress and SGLT2. Also, we highlighted different preclinical studies of SGLT2 inhibitors against TLR2/4 signaling in various kidney diseases. Moreover, we discuss the observational and interventional evidence about the relation between TLR2/4, ER stress, and SGLT2, which may represent the TLR2/4 as a potential therapeutic target for kidney disease.
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17
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Sun X, Wang G. Renal outcomes with sodium-glucose cotransporters 2 inhibitors. Front Endocrinol (Lausanne) 2022; 13:1063341. [PMID: 36531469 PMCID: PMC9752889 DOI: 10.3389/fendo.2022.1063341] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 11/08/2022] [Indexed: 12/05/2022] Open
Abstract
Diabetic nephropathy (DN) is one of the most serious complications of diabetes. Therefore, delaying and preventing the progression of DN becomes an important goal in the clinical treatment of type 2 diabetes mellitus. Recent studies confirm that sodium-glucose cotransporters 2 inhibitors (SGLT2is) have been regarded as effective glucose-lowering drugs with renal protective effect. In this review, we summarize in detail the present knowledge of the effects of SGLT2is on renal outcomes by analyzing the experimental data in preclinical study, the effects of SGLT2is on estimated glomerular flitration rates (eGFRs) and urinary albumin-creatinine ratios (UACRs) from clinical trials and observational studies, and renal events (such as renal death or renal failure requiring renal replacement therapy) in some large prospective cardiovaslucar outcomes trials. The underlying mechanisms for renoprotective activity of SGLT2is have been demondtrated in multiple diabetic and nondiabetic animal models including kidney-specific effects and secondary kidney effects related to amelioration in blood glucose and blood pressure. In conclusion, these promising results show that SGLT2is act beneficially in terms of the kidney for diabetic patients.
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Affiliation(s)
| | - Guohong Wang
- Department of Geriatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, China
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18
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Yaribeygi H, Maleki M, Reiner Ž, Jamialahmadi T, Sahebkar A. Mechanistic View on the Effects of SGLT2 Inhibitors on Lipid Metabolism in Diabetic Milieu. J Clin Med 2022; 11:6544. [PMID: 36362772 PMCID: PMC9653639 DOI: 10.3390/jcm11216544] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 10/28/2022] [Accepted: 11/02/2022] [Indexed: 08/30/2023] Open
Abstract
Chronic hyperglycemia induces pathophysiologic pathways with negative effects on the metabolism of most substrates as well as lipids and lipoproteins, and thereby induces dyslipidemia. Thus, the diabetic milieu is commonly accompanied by different levels of atherogenic dyslipidemia, which is per se a major risk factor for subsequent complications such as atherosclerosis, coronary heart disease, acute myocardial infarction, ischemic stroke, and nephropathy. Therefore, readjusting lipid metabolism in the diabetic milieu is a major goal for preventing dyslipidemia-induced complications. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a class of relatively newly introduced antidiabetes drugs (including empagliflozin, canagliflozin, dapagliflozin, etc.) with potent hypoglycemic effects and can reduce blood glucose by inducing glycosuria. However, recent evidence suggests that they could also provide extra-glycemic benefits in lipid metabolism. It seems that they can increase fat burning and lipolysis, normalizing the lipid metabolism and preventing or improving dyslipidemia. Nevertheless, the exact mechanisms involved in this process are not well-understood. In this review, we tried to explain how these drugs could regulate lipid homeostasis and we presented the possible involved cellular pathways supported by clinical evidence.
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Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
| | - Mina Maleki
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Željko Reiner
- Department of Internal Medicine, University Hospital Center Zagreb, 1000 Zagreb, Croatia
| | - Tannaz Jamialahmadi
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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19
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Theofilis P, Vordoni A, Kalaitzidis RG. Oxidative Stress Management in Cardiorenal Diseases: Focus on Novel Antidiabetic Agents, Finerenone, and Melatonin. Life (Basel) 2022; 12:1663. [PMID: 36295098 PMCID: PMC9605243 DOI: 10.3390/life12101663] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 10/15/2022] [Accepted: 10/19/2022] [Indexed: 11/16/2022] Open
Abstract
Oxidative stress is characterized by excessive production of reactive oxygen species together with exhausted antioxidant defenses. This constitutes a main pathophysiologic process that is implicated in cardiovascular and renal diseases. In particular, enhanced oxidative stress may lead to low-density lipoprotein accumulation and oxidation, endothelial cell activation, adhesion molecule overexpression, macrophage activation, and foam cell formation, promoting the development and progression of atherosclerosis. The deleterious kidney effects of oxidative stress are numerous, including podocytopathy, mesangial enlargement, renal hypertrophy, tubulointerstitial fibrosis, and glomerulosclerosis. The prominent role of oxidative mechanisms in cardiorenal diseases may be counteracted by recently developed pharmacotherapies such as novel antidiabetic agents and finerenone. These agents have demonstrated significant antioxidant activity in preclinical and clinical studies. Moreover, the use of melatonin as a treatment in this field has been experimentally investigated, with large-scale clinical studies being awaited. Finally, clinical implications and future directions in this field are presented.
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Affiliation(s)
| | | | - Rigas G. Kalaitzidis
- Center for Nephrology “G. Papadakis”, General Hospital of Nikaia-Piraeus Agios Panteleimon, 18454 Piraeus, Greece
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20
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Zhan X, Cheng L, Huo N, Yu L, Liu C, Liu T, Li G, Fu H. Sodium-glucose cotransporter-2 inhibitor alleviated atrial remodeling in STZ-induced diabetic rats by targeting TLR4 pathway. Front Cardiovasc Med 2022; 9:908037. [PMID: 36148071 PMCID: PMC9485554 DOI: 10.3389/fcvm.2022.908037] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 08/05/2022] [Indexed: 11/23/2022] Open
Abstract
PURPOSE The mechanism of sodium-glucose cotransporter-2 inhibitor (SGLT-2i) reducing the incidence of atrial fibrillation remains unclear. We hypothesize that sodium-glucose cotransporter-2 inhibitor alleviated atrial remodeling in STZ-induced diabetic rats by targeting TLR4 pathway. METHODS A total of 42 rats were randomly assigned into three groups: control group (CON group); diabetes group (DM group): diabetes mellitus rats were established by 65 mg/kg streptozotocin (STZ) intraperitoneal injection; and diabetes + dapagliflozin group (DM + DAPA group): diabetic rats were given DAPA gavage administration (DAPA 2mg/kg/d for 4 weeks by gavage administration), 14 rats in each group. Epicardial multiple-lead recording and intracardiac electrophysiology studies were performed to investigate the electrical remodeling in the heart and the atrial fibrillation inducibility in each group. Western blot analysis and real-time PCR were used to determine the protein and mRNA expression of toll-like receptor 4 (TLR4), interleukin receptor-associated kinase 1 (IRAK1), tumor necrosis factor receptor-associated factor 6 (TRAF6), nuclear factor-kappa B (NF-κB), and type I collagen (collagen I). RESULTS Compared with rats in CON group, rats in DM group showed marked myocardial fibrosis, ectopic pacing excitement, reduced conduction velocity, decreased cardiac function. TLR4/IRAK1/TRAF6/NF-κB, collagen I proteins expressions and incidence of atrial fibrillation (27.3%) were increased in DM group. Parts of these changes were reversed by treatment of DAPA. Incidence of atrial fibrillation was decreased in DM + DAPA group (2.8%). CONCLUSIONS SGLT-2i dapagliflozin may prevent diabetic rats' atrial remodeling and reduce the inducibility of atrial fibrillation partly by targeting TLR4/IRAK1/TRAF6/NF-κB inflammatory pathway.
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Affiliation(s)
| | | | | | | | | | | | | | - Huaying Fu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China
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21
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Chu C, Delić D, Alber J, Feger M, Xiong Y, Luo T, Hasan AA, Zeng S, Gaballa MMS, Chen X, Yin L, Klein T, Elitok S, Krämer BK, Föller M, Hocher B. Head-to-head comparison of two SGLT-2 inhibitors on AKI outcomes in a rat ischemia-reperfusion model. Biomed Pharmacother 2022; 153:113357. [PMID: 35792391 DOI: 10.1016/j.biopha.2022.113357] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 06/23/2022] [Accepted: 06/28/2022] [Indexed: 12/24/2022] Open
Abstract
The CREDENCE trial testing canagliflozin and the EMPA-REG OUTCOME trial testing empagliflozin suggest different effects on acute kidney injury (AKI). AKI diagnosis was mainly made based on changes of serum creatinine (sCr) although this also reflect mode of action of SGLT-2 inhibitors. We analyzed both compounds in a rat AKI model. The renal ischemia-reperfusion injury (I/R) model was used. Four groups were analyzed: sham, I/R+placebo, I/R+canagliflozin (30 mg/kg/day), I/R+ empagliflozin (10 mg/kg/day). Glucose excretion was comparable in both treatment groups indicating comparable SGLT-2 inhibition. Comparing GFR surrogate markers after I/R (sCr and blood urea nitrogen (BUN)), sCr peaked 24 h after I/R, BUN after 48 h, respectively, in the placebo treated I/R group. At all investigated time points after I/R sCr and BUN was higher in the I/R + canagliflozin group as compared to placebo treated rats, whereas the empagliflozin group did not differ from the placebo group. I/R led to tubular dilatation and necrosis. Empagliflozin was able to reduce that finding whereas canagliflozin had no effect. Treatment with empagliflozin also resulted in a significant reduction in an improved inflammatory score (p = 0.006). Renal expression of kidney injury molecule-1 (KIM-1) increased after I/R and empagliflozin but not canagliflozin significantly alleviated KIM-1 expression. I/R reduced urinary miR-26a excretion. Empagliflozin but not canagliflozin was able to restore normal levels of urinary miR-26a. This study in an AKI model confirmed safety data in the EMPA-REG OUTCOME trial suggesting that empagliflozin might reduce AKI risk. The empagliflozin effects on KIM-1 and miR-26a might indicate beneficial regulation of inflammation. These data should stimulate clinical studies with AKI risk as primary endpoint.
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Affiliation(s)
- Chang Chu
- Department of Nephrology, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany; Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; The First Clinical Medical College of Jinan University, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Denis Delić
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; Translational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr. 65, 88397 Biberach, Germany
| | - Jana Alber
- University of Hohenheim, Department of Physiology, Stuttgart, Germany
| | - Martina Feger
- University of Hohenheim, Department of Physiology, Stuttgart, Germany
| | - Yingquan Xiong
- Department of Nephrology, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany; Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany
| | - Ting Luo
- The First Clinical Medical College of Jinan University, The First Affiliated Hospital of Jinan University, Guangzhou, China; Nephrology Division, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Ahmed A Hasan
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Egypt
| | - Shufei Zeng
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany
| | - Mohamed M S Gaballa
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; Faculty of Veterinary Medicine, Benha University, Toukh, Egypt
| | - Xin Chen
- Department of Nephrology, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany; Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; The First Clinical Medical College of Jinan University, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Lianghong Yin
- The First Clinical Medical College of Jinan University, The First Affiliated Hospital of Jinan University, Guangzhou, China.
| | - Thomas Klein
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach, Germany
| | - Saban Elitok
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; Klinikum Ernst von Bergmann gGmbH, Potsdam, Germany
| | - Bernhard K Krämer
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; European Center for Angioscience, Medical Faculty Mannheim, University of Heidelberg, Germany
| | - Michael Föller
- University of Hohenheim, Department of Physiology, Stuttgart, Germany
| | - Berthold Hocher
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China; IMD Institut für Medizinische Diagnostik Berlin-Potsdam GbR, Berlin, Germany.
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22
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Experimental models of acute kidney injury for translational research. Nat Rev Nephrol 2022; 18:277-293. [PMID: 35173348 DOI: 10.1038/s41581-022-00539-2] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2022] [Indexed: 12/20/2022]
Abstract
Preclinical models of human disease provide powerful tools for therapeutic discovery but have limitations. This problem is especially apparent in the field of acute kidney injury (AKI), in which clinical trial failures have been attributed to inaccurate modelling performed largely in rodents. Multidisciplinary efforts such as the Kidney Precision Medicine Project are now starting to identify molecular subtypes of human AKI. In addition, over the past decade, there have been developments in human pluripotent stem cell-derived kidney organoids as well as zebrafish, rodent and large animal models of AKI. These organoid and AKI models are being deployed at different stages of preclinical therapeutic development. However, the traditionally siloed, preclinical investigator-driven approaches that have been used to evaluate AKI therapeutics to date rarely account for the limitations of the model systems used and have given rise to false expectations of clinical efficacy in patients with different AKI pathophysiologies. To address this problem, there is a need to develop more flexible and integrated approaches, involving teams of investigators with expertise in a range of different model systems, working closely with clinical investigators, to develop robust preclinical evidence to support more focused interventions in patients with AKI.
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23
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Miura T, Kuno A, Tanaka M. Diabetes modulation of the myocardial infarction- acute kidney injury axis. Am J Physiol Heart Circ Physiol 2022; 322:H394-H405. [PMID: 35089809 DOI: 10.1152/ajpheart.00639.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Since there is crosstalk in functions of the heart and kidney, acute or chronic injury in one of the two organs provokes adaptive and/or maladaptive responses in both organs, leading to cardiorenal syndrome (CRS). Acute kidney injury (AKI) induced by acute heart failure is referred to as type 1 CRS, and a frequent cause of this type of CRS is acute myocardial infarction (AMI). Diabetes mellitus increases the risk of AMI and also the risk of AKI of various causes. However, there have been only a few studies in which animal models of diabetes were used to examine how diabetes modulates AMI-induced AKI. In this review, we summarize findings regarding the mechanisms of type 1 CRS and the impact of diabetes on both AMI and renal susceptibility to AKI and we discuss mechanisms by which diabetes modulates AMI-induced AKI. Hemodynamic alterations induced by AMI could be augmented by diabetes via its detrimental effect on infarct size and contractile function of the non-infarcted region in the heart. Diabetes increases susceptibility of renal cells to hypoxia and oxidative stress by modulation of signaling pathways that regulate cell survival and autophagy. Recent studies have shown that diabetes mellitus even at early stage of cardiomyopathy/nephropathy predisposes the kidney to AMI-induced AKI, in which activation of toll-like receptors and reactive oxygen species derived from NADPH oxidases are involved. Further analysis of crosstalk between diabetic cardiomyopathy and diabetic kidney disease is necessary for obtaining a more comprehensive understanding of modulation of the AMI-AKI axis by diabetes.
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Affiliation(s)
- Tetsuji Miura
- Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, Sapporo, Japan.,Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Atsushi Kuno
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Pharmacology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Marenao Tanaka
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
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Liu H, Sridhar VS, Boulet J, Dharia A, Khan A, Lawler PR, Cherney DZI. Cardiorenal protection with SGLT2 inhibitors in patients with diabetes mellitus: from biomarkers to clinical outcomes in heart failure and diabetic kidney disease. Metabolism 2022; 126:154918. [PMID: 34699838 DOI: 10.1016/j.metabol.2021.154918] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 10/14/2021] [Accepted: 10/19/2021] [Indexed: 12/23/2022]
Abstract
Type 2 diabetes (T2D) is one of the most common causes of chronic kidney disease (CKD) and cardiovascular (CV) disease. Until recently, glycemic and BP control were the cornerstones for preventing progression of CKD and CV disease associated with T2D. However, there has been a paradigm shift in treatment since the publication of the first clinical trial demonstrating benefits of sodium glucose cotransporter 2 (SGLT2) inhibitors in 2015. SGLT2 inhibitors have been shown to reduce the risk of major adverse CV events and progression of kidney disease in the setting of T2D. However, the elucidation of mechanisms of underlying these clinical benefits is the subject of ongoing investigation. Experimental studies have shown that SGLT2 inhibitors have diverse pleiotropic effects such as modulation of neurohormones such as the renin-angiotensin-aldosterone system, increasing hematocrit, altering energy substrate use, and attenuating systemic inflammation and oxidative stress, all of which have been implicated in the CV and kidney protective effects of SGLT2 inhibitors. In this review, we highlight biomarkers linked with diabetic kidney disease and heart failure and discuss how SGLT2 inhibitor-associated changes potentially mediate the cardiorenal protection observed with these therapies.
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Affiliation(s)
- Hongyan Liu
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
| | - Vikas S Sridhar
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Jacinthe Boulet
- Department of Medicine, Division of Cardiology, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada
| | - Atit Dharia
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada
| | - Abid Khan
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada
| | - Patrick R Lawler
- Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada; Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ON, Canada; Division of Cardiology and Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
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25
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Ravindran S, Munusamy S. Renoprotective mechanisms of sodium-glucose co-transporter 2 (SGLT2) inhibitors against the progression of diabetic kidney disease. J Cell Physiol 2021; 237:1182-1205. [PMID: 34713897 DOI: 10.1002/jcp.30621] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 10/02/2021] [Accepted: 10/08/2021] [Indexed: 12/19/2022]
Abstract
Sodium-glucose co-transporter 2 inhibitors (SGLT2-Is) have emerged as a promising class of antidiabetic drugs with cardioprotective and renoprotective effects in patients with type 2 diabetes (T2D). The sodium-glucose co-transporters 1 and 2 (SGLT 1 and SGLT2) located in the renal proximal tubules are responsible for glucose reabsorption from the glomerular filtrate back into the systemic circulation. Inhibition of SGLT2, which accounts for about 90% of the glucose reabsorption, leads to a significant reduction in blood glucose levels and a concomitant increase in the urinary excretion of glucose (glycosuria). Multiple mechanisms contribute to the nephroprotective effects of SGLT2-Is in T2D patients. These include: (1) Restoration of the tubuloglomerular feedback by increasing sodium delivery at macula densa, leading to afferent arteriolar constriction and reduced glomerular hyperfiltration, (2) Decreased activation of the intra-renal renin-angiotensin-aldosterone system, which also contributes to reducing glomerular hyperfiltration, (3) Increased production of ketone bodies, which serves as an alternate fuel for adenosine triphosphate production in mitochondria, which helps in attenuating inflammation, and (4) Protection against hypoxia, oxidative stress, and fibrosis. This review elaborates on the key mechanisms that underlie the nephroprotective effects and the adverse effects of SGLT2-Is in T2D patients with progressive diabetic kidney disease.
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Affiliation(s)
| | - Shankar Munusamy
- Department of Pharmaceutical and Administrative Sciences, Drake University College of Pharmacy and Health Sciences, Des Moines, Iowa, USA
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26
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Deger M, Kaya B, Akdogan N, Kaplan HM, Bagir E, Izol V, Aridogan IA. Protective effect of dapagliflozin against cyclosporine A-induced nephrotoxicity. Drug Chem Toxicol 2021; 45:2637-2643. [PMID: 34565275 DOI: 10.1080/01480545.2021.1979996] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
This study aimed to reveal the possible protective effect of dapagliflozin (DAPA) against acute kidney damage due to cyclosporine A (CsA). Thirty-two mice with an eight-week-old Balb\c albino strain were divided into four groups: control group, CsA group, DAPA group, and CsA + DAPA group. On day 9 of treatment, the animals were decapitated, and bilateral nephrectomy was performed. Oxidative stress and apoptosis were evaluated with caspase-3 activity, total oxidant status (TOS), total antioxidant status (TAS), malondialdehyde (MDA), myeloperoxidase (MPO), B-cell lymphoma-2 (Bcl-2), and Bcl-2-associated X protein (Bax) in the right kidney resection material. The left kidney resection material was evaluated histopathologically. CsA increased caspase-3 activity, Bax, TOS, MDA, TAS, and MPO levels, and the administration of DAPA with CsA significantly reduced this increase in levels (p < 0.001, p < 0.001, p < 0.001, p < 0.001, p < 0.001, and p < 0.001, respectively). CsA decreased Bcl-2 levels, and administration of CsA + DAPA significantly increased Bcl-2 levels compared with only CsA administration (p < 0.001). Additionally, administration of DAPA significantly reduced the histopathological findings (parenchymal inflammation, hyaline cast formation, vacuolization, and lysis of renal tubular cells) caused by CsA. DAPA reduces oxidative stress, apoptosis, and histopathological damage caused by CsA in renal tissue.
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Affiliation(s)
- Mutlu Deger
- Department of Urology, Faculty of Medicine, Çukurova University, Adana, Turkey
| | - Bulent Kaya
- Department of Nephrology, Faculty of Medicine, Çukurova University, Adana, Turkey
| | - Nebil Akdogan
- Department of Urology, Faculty of Medicine, Çukurova University, Adana, Turkey
| | - Halil Mahir Kaplan
- Department of Pharmacology, Faculty of Medicine, Cukurova University, Adana, Turkey
| | - Emine Bagir
- Department of Pathology, Faculty of Medicine, Çukurova University, Adana, Turkey
| | - Volkan Izol
- Department of Urology, Faculty of Medicine, Çukurova University, Adana, Turkey
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Morsy MA, Khalaf HM, Rifaai RA, Bayoumi AMA, Khalifa EMMA, Ibrahim YF. Canagliflozin, an SGLT-2 inhibitor, ameliorates acetic acid-induced colitis in rats through targeting glucose metabolism and inhibiting NOX2. Biomed Pharmacother 2021; 141:111902. [PMID: 34328119 DOI: 10.1016/j.biopha.2021.111902] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 06/29/2021] [Accepted: 07/06/2021] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Inflammatory bowel disease is defined as chronic noninfectious inflammation of the gastrointestinal tract, including ulcerative colitis and Crohn's disease. Its incidence and predominance have increased globally, with no effective agents for preventing its recurrence or treatment until now. AIM The current study aimed to investigate the possible role of canagliflozin (CANA), a sodium-glucose co-transporter-2 inhibitor (SGLT-2), to prevent and treat acetic acid (AA)-induced colitis in a rat model. METHODS Colitis was induced in male Wistar rats by intrarectal instillation of 1 ml of 4% (v/v) AA. Rats were treated orally with either CANA (30 mg/kg/day, p.o.) for 10 days before or after colitis induction or sulfasalazine (360 mg/kg/day, p.o.) for 10 days before colitis induction. RESULTS AA resulted in a significant increase in disease activity index, colonic weight over length ratio, colon macroscopic damage score, and histological signs of colitis. All of these effects were significantly decreased by CANA administration. Additionally, CANA markedly inhibited AA-induced oxidative stress and inflammatory responses by significantly reducing the up-regulated levels in malondialdehyde, total nitrite, NF-κB, interleukin-1β, and TNF-α, and significantly increasing the down-regulated levels in reduced glutathione, superoxide dismutase, and interleukin-10. CANA significantly inhibited caspase-3 level while rescued survivin expression in colons. Finally, CANA reduced the elevated levels of pyruvic acid and G6PDH activity, as well as the levels of p22phox and NOX2 in the AA-induced colitis. CONCLUSION Our findings provide novel evidence that CANA has protective and therapeutic effects against AA-induced colitis by the impact of its antioxidant, anti-inflammatory, and anti-apoptotic effects.
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Affiliation(s)
- Mohamed A Morsy
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia; Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia 61511, Egypt.
| | - Hanaa M Khalaf
- Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia 61511, Egypt
| | - Rehab A Rifaai
- Department of Histology and Cell Biology, Faculty of Medicine, Minia University, El-Minia 61511, Egypt
| | - Asmaa M A Bayoumi
- Department of Biochemistry, Faculty of Pharmacy, Minia University, El-Minia 61511, Egypt
| | - Esraa M M A Khalifa
- Department of Biochemistry, Faculty of Pharmacy, Deraya University, El-Minia 61111, Egypt
| | - Yasmine F Ibrahim
- Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia 61511, Egypt
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Shibata S, Moniwa N, Kuno A, Kimura A, Ohwada W, Sugawara H, Gocho Y, Tanaka M, Yano T, Furuhashi M, Tanno M, Miki T, Miura T. Involvement of necroptosis in contrast-induced nephropathy in a rat CKD model. Clin Exp Nephrol 2021; 25:708-717. [PMID: 33728555 DOI: 10.1007/s10157-021-02048-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 03/08/2021] [Indexed: 11/24/2022]
Abstract
BACKGROUND The risk of contrast-induced nephropathy (CIN) is high in patients with chronic kidney disease (CKD). However, the mechanism of CIN in CKD is not fully understood. Here, we prepared a clinically relevant model of CIN and examined the role of necroptosis, which potentially cross-talks with autophagy, in CIN. METHODS In Sprague-Dawley rats, CKD was induced by subtotal nephrectomy (SNx, 5/6 nephrectomy) 4 weeks before induction of CIN. CIN was induced by administration of a contrast medium (CM), iohexol, following administration of indomethacin and N-omega-Nitro-L-arginine methyl ester. Renal function and tissue injuries were assessed 48 h after CM injection. RESULTS Serum creatinine (s-Cre) and BUN were increased from 0.28 ± 0.01 to 0.52 ± 0.02 mg/dl and from 15.1 ± 0.7 to 29.2 ± 1.2 mg/dl, respectively, after SNx alone. CM further increased s-Cre and BUN to 0.69 ± 0.03 and 37.2 ± 2.1, respectively. In the renal tissue after CM injection, protein levels of receptor-interacting serine/threonine-protein kinase (RIP) 1, RIP3, cleaved caspase 3, and caspase 8 were increased by 64 ~ 212%, while there was reduction in LC3-II and accumulation of p62. Necrostatin-1, an RIP1 inhibitor, administered before and 24 h after CM injection significantly suppressed elevation of s-Cre, BUN and urinary albumin levels, kidney injury molecule-1 expression and infiltration of CD68-positive macrophages in renal tissues after CM injection. CONCLUSION The results suggest that necroptosis of proximal tubular cells contributes to CIN in CKD and that suppression of protective autophagy by pro-necroptotic signaling may also be involved.
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Affiliation(s)
- Satoru Shibata
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Norihito Moniwa
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan.
| | - Atsushi Kuno
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Ayumu Kimura
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Wataru Ohwada
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Hirohito Sugawara
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Yufu Gocho
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Marenao Tanaka
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Toshiyuki Yano
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Masato Furuhashi
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Masaya Tanno
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Takayuki Miki
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Tetsuji Miura
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan
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Canagliflozin protects against sepsis capillary leak syndrome by activating endothelial α1AMPK. Sci Rep 2021; 11:13700. [PMID: 34211080 PMCID: PMC8249425 DOI: 10.1038/s41598-021-93156-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 06/16/2021] [Indexed: 02/08/2023] Open
Abstract
Sepsis capillary leak syndrome (SCLS) is an independent prognostic factor for poor sepsis outcome. We previously demonstrated that α1AMP-activated protein kinase (α1AMPK) prevents sepsis-induced vascular hyperpermeability by mechanisms involving VE-cadherin (VE-Cad) stabilization and activation of p38 mitogen activated protein kinase/heat shock protein of 27 kDa (p38MAPK/HSP27) pathway. Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, has recently been proven to activate AMPK in endothelial cells. Therefore, we hypothesized that canagliflozin could be of therapeutic potential in patients suffering from SCLS. We herein report that canagliflozin, used at clinically relevant concentrations, counteracts lipopolysaccharide-induced vascular hyperpermeability and albumin leakage in wild-type, but not in endothelial-specific α1AMPK-knockout mice. In vitro, canagliflozin was demonstrated to activate α1AMPK/p38MAPK/HSP27 pathway and to preserve VE-Cad’s integrity in human endothelial cells exposed to human septic plasma. In conclusion, our data demonstrate that canagliflozin protects against SCLS via an α1AMPK-dependent pathway, and lead us to consider novel therapeutic perspectives for this drug in SCLS.
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Liu H, Sridhar VS, Lovblom LE, Lytvyn Y, Burger D, Burns K, Brinc D, Lawler PR, Cherney DZI. Markers of Kidney Injury, Inflammation, and Fibrosis Associated With Ertugliflozin in Patients With CKD and Diabetes. Kidney Int Rep 2021; 6:2095-2104. [PMID: 34386658 PMCID: PMC8343791 DOI: 10.1016/j.ekir.2021.05.022] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 05/12/2021] [Accepted: 05/17/2021] [Indexed: 12/16/2022] Open
Abstract
Introduction Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve cardiovascular and kidney outcomes through mechanisms that are incompletely understood. In this exploratory post-hoc analysis of the VERTIS RENAL trial, we report the association between the SGLT2 inhibitor, ertugliflozin, and markers of kidney injury, inflammation, and fibrosis in participants with type 2 diabetes (T2D) and stage 3 chronic kidney disease (CKD). Methods Participants were randomized to ertugliflozin (5 or 15 mg/d) or placebo, and plasma samples for biomarker analysis were collected at baseline, 26 weeks, and 52 weeks. Results Ertugliflozin-treated participants had lower plasma levels of kidney injury molecule-1 (KIM-1) at 26 weeks (P = 0.044) and 52 weeks (P = 0.007) and higher eotaxin-1 at 52 weeks (P = 0.007) postrandomization compared with placebo. The change in KIM-1 was not associated with the baseline urine albumin to creatinine ratio (UACR) or the estimated glomerular filtration rate (eGFR, P interaction > 0.05). Additionally, the change in KIM-1 was positively correlated with the change in UACR in participants treated with ertugliflozin (P = 0.0071). No other significant associations between ertugliflozin and changes in the markers of tubular injury, inflammation, fibrosis, oxidative stress, and endothelial dysfunction were observed. Conclusion In conclusion, in participants with T2D and stage 3 CKD, ertugliflozin was associated with a sustained lowering of the tubular injury marker KIM-1 regardless of baseline kidney function.
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Affiliation(s)
- Hongyan Liu
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.,Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
| | - Vikas S Sridhar
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.,Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.,Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Leif Erik Lovblom
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
| | - Yuliya Lytvyn
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.,Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Dylan Burger
- Division of Nephrology, Department of Medicine, Ottawa Hospital Research Institute, Kidney Research Centre, University of Ottawa, Ottawa, Ontario, Canada
| | - Kevin Burns
- Division of Nephrology, Department of Medicine, Ottawa Hospital Research Institute, Kidney Research Centre, University of Ottawa, Ottawa, Ontario, Canada
| | - Davor Brinc
- Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Patrick R Lawler
- Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.,Ted Rogers Centre for Heart Research, University of Toronto, Toronto, Ontario, Canada.,Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.,Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.,Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.,Department of Medicine, University of Toronto, Toronto, Ontario, Canada.,Department of Physiology, University of Toronto, Toronto, Ontario, Canada
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Qi H, Gu L, Xu D, Liu K, Zhou M, Wang Y, Wang X, Li Y, Qi J. β-Hydroxybutyrate inhibits cardiac microvascular collagen 4 accumulation by attenuating oxidative stress in streptozotocin-induced diabetic rats and high glucose treated cells. Eur J Pharmacol 2021; 899:174012. [PMID: 33727057 DOI: 10.1016/j.ejphar.2021.174012] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Revised: 02/19/2021] [Accepted: 02/28/2021] [Indexed: 12/19/2022]
Abstract
Accumulation of collagen 4 (COL4) and thickened basement membrane are features of diabetic cardiac microvascular fibrosis that may be induced by oxidative stress. The ketone body β-hydroxybutyrate exhibits various cardiovascular protective effects, however its mechanism remains to be clarified. In the current study, the effects of β-hydroxybutyrate on cardiac microvascular fibrosis and COL4 accumulation were evaluated in streptozotocin-induced diabetic rats and in high glucose (HG) treated human cardiac microvascular endothelial cells (HCMECs). Generations of inducible nitric oxide synthase (iNOS) and copper-zinc superoxide dismutase (Cu/Zn-SOD), and the amount of nitrotyrosine (NT) were measured in vivo and in vitro. Ten weeks of β-hydroxybutyrate treatment (160, 200 and 240 mg/kg/d) attenuated cardiac microvascular fibrosis and inhibited cardiac COL4 generation and microvascular distribution in diabetic rats. Furthermore, β-hydroxybutyrate promoted cardiac Cu/Zn-SOD generation and reduced NT content, without reducing iNOS generation in diabetic rats. In HCMECs, stimulation with HG induced excess generation of COL4 via peroxynitrite. β-Hydroxybutyrate treatment (2, 4, 6 mM) attenuated HG-stimulated COL4 accumulation in a concentration-dependent manner. Similarly, 4 mM β-hydroxybutyrate promoted Cu/Zn-SOD generation and reduced NT content, without affecting excess iNOS generation in HG-stimulated HCMECs. In conclusion, this study showed that β-hydroxybutyrate promoted Cu/Zn-SOD generation, reduced peroxynitrite and inhibited cardiac microvascular COL4 accumulation in diabetes.
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Affiliation(s)
- Huanli Qi
- Department of Biochemistry, College of Integrated Chinese and Western Medicine, Hebei Medical University, Shijiazhuang, PR China
| | - Lihui Gu
- Department of Molecular Biology, Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, Shijiazhuang, PR China
| | - Dongmei Xu
- Department of Food and drug Engineering, Shijiazhuang University of Applied Technology, Shijiazhuang, PR China
| | - Kun Liu
- Department of Biochemistry, College of Integrated Chinese and Western Medicine, Hebei Medical University, Shijiazhuang, PR China
| | - Mingjie Zhou
- Department of Biochemistry, College of Integrated Chinese and Western Medicine, Hebei Medical University, Shijiazhuang, PR China
| | - Yu Wang
- Department of Molecular Biology, Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, Shijiazhuang, PR China
| | - Xiujuan Wang
- Department of Biochemistry, College of Integrated Chinese and Western Medicine, Hebei Medical University, Shijiazhuang, PR China
| | - Yanning Li
- Department of Biochemistry, College of Integrated Chinese and Western Medicine, Hebei Medical University, Shijiazhuang, PR China; Department of Molecular Biology, Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, Shijiazhuang, PR China.
| | - Jinsheng Qi
- Department of Biochemistry, College of Integrated Chinese and Western Medicine, Hebei Medical University, Shijiazhuang, PR China.
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32
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Shikata K. Recent evidence in the etiology and treatment for diabetic kidney disease. J Diabetes Investig 2021; 12:694-696. [PMID: 33031619 PMCID: PMC8089001 DOI: 10.1111/jdi.13433] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 10/05/2020] [Accepted: 10/06/2020] [Indexed: 12/21/2022] Open
Abstract
Etiology and therapeutic targets of diabetic nephropathy.
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Affiliation(s)
- Kenichi Shikata
- Center for Innovative Clinical MedicineOkayama University HospitalOkayamaJapan
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Gómez-Sámano MÁ, Vargas-Abonce VP, Martínez-Sánchez FD, Palacios-Báez L, Vera-Zertuche JM, Navarro-Flores MF, Morales-García MG, Fonseca-Correa JI, Zuarth-Vázquez JM, Vega-Vega O, Correa-Rotter R, Rincón-Pedrero R, Morales-Buenrostro LE, Alberú-Gómez J, Ramírez-González JB, Pacheco-Domínguez RL, López-Cervantes M, Mendoza-de-la-Garza MDLÁ, Baeza-Arias YV, Espinosa-Cuevas Á, López-Carrasco G, López-Estrada A, Guillén-Pineda LE, Gómez-Pérez FJ, Cuevas-Ramos D. Fibroblast growth factor 21 is associated with increased serum total antioxidant capacity and oxidized lipoproteins in humans with different stages of chronic kidney disease. Ther Adv Endocrinol Metab 2021; 12:20420188211001160. [PMID: 33854753 PMCID: PMC8010821 DOI: 10.1177/20420188211001160] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 02/12/2021] [Indexed: 12/12/2022] Open
Abstract
Background and aims Oxidative stress (OS) induces the production of fibroblast growth factor 21 (FGF21). Previous data have revealed that FGF21 protects cells from OS injury and death, making it a potential therapeutic option for many diseases with increased OS. However, the association of this growth factor with OS markers in humans with chronic kidney disease (CKD) remains unknown. This study aims to evaluate the association of serum FGF21 with serum total antioxidant capacity (TAC) and oxidized low-density lipoproteins (OxLDL) in subjects in different stages of kidney disease. Methods This is a cross-sectional study that included 382 subjects with different stages of CKD, irrespective of type 2 diabetes (T2D) diagnosis. Associations of serum FGF21 with OxLDL, TAC, sex, age, body mass index (BMI), fasting plasma glucose, estimated glomerular filtration rate (eGFR), T2D, and smoking, were evaluated through bivariate and partial correlation analyses. Independent associations of these variables with serum FGF21 were evaluated using multiple linear regression analysis. Results Serum FGF21 was significantly and positively correlated with age (r = 0.236), TAC (lnTAC) (r = 0.217), and negatively correlated with eGFR (r = -0.429) and male sex (r = -0.102). After controlling by age, sex, BMI, T2D, smoking, and eGFR; both TAC and OxLDL were positively correlated with FGF21 (r = 0.117 and 0.158 respectively, p < 0.05). Using multiple linear regression analysis, eGFR, male sex, T2D, OxLDL, and TAC were independently associated with serum FGF21 (STDβ = -0.475, 0.162, -0.153, 0.142 and 0.136 respectively; p < 0.05 for all) adjusted for age, BMI, smoking, and fasting plasma glucose. Conclusion A positive association between serum FGF21 and OS has been found independently of renal function in humans. Results from the present study provide novel information for deeper understanding of the role of FGF21 in OS in humans with CKD and T2D; mechanistic studies to explain the association of serum FGF21 with oxidative stress in CKD are needed.
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Affiliation(s)
| | | | | | - Lucía Palacios-Báez
- Instituto Nacional de Ciencias Medicas y
Nutricion Salvador Zubiran, Mexico City, Mexico
| | | | | | | | | | | | - Olynka Vega-Vega
- Instituto Nacional de Ciencias Medicas y
Nutricion Salvador Zubiran, Mexico City, Mexico
| | - Ricardo Correa-Rotter
- Instituto Nacional de Ciencias Medicas y
Nutricion Salvador Zubiran, Mexico City, Mexico
| | - Rodolfo Rincón-Pedrero
- Instituto Nacional de Ciencias Medicas y
Nutricion Salvador Zubiran, Mexico City, Mexico
| | | | - Josefina Alberú-Gómez
- Instituto Nacional de Ciencias Medicas y
Nutricion Salvador Zubiran, Mexico City, Mexico
| | | | | | - Malaquías López-Cervantes
- Department of Preventive Medicine and Public
Health, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | | | | | | | | | - Angelina López-Estrada
- Instituto Nacional de Ciencias Medicas y
Nutricion Salvador Zubiran, Mexico City, Mexico
| | | | | | - Daniel Cuevas-Ramos
- Department of Endocrinology and Metabolism,
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Vasco
de Quiroga # 15, Sección XVI Tlalpan 14000, Mexico City, Mexico
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Nishinarita R, Niwano S, Niwano H, Nakamura H, Saito D, Sato T, Matsuura G, Arakawa Y, Kobayashi S, Shirakawa Y, Horiguchi A, Ishizue N, Igarashi T, Yoshizawa T, Oikawa J, Hara Y, Katsumura T, Kishihara J, Satoh A, Fukaya H, Sakagami H, Ako J. Canagliflozin Suppresses Atrial Remodeling in a Canine Atrial Fibrillation Model. J Am Heart Assoc 2021; 10:e017483. [PMID: 33399004 PMCID: PMC7955321 DOI: 10.1161/jaha.119.017483] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Background Recent clinical trials have demonstrated the possible pleiotropic effects of SGLT2 (sodium–glucose cotransporter 2) inhibitors in clinical cardiovascular diseases. Atrial electrical and structural remodeling is important as an atrial fibrillation (AF) substrate. Methods and Results The present study assessed the effect of canagliflozin (CAN), an SGLT2 inhibitor, on atrial remodeling in a canine AF model. The study included 12 beagle dogs, with 10 receiving continuous rapid atrial pacing and 2 acting as the nonpacing group. The 10 dogs that received continuous rapid atrial pacing for 3 weeks were subdivided as follows: pacing control group (n=5) and pacing+CAN (3 mg/kg per day) group (n=5). The atrial effective refractory period, conduction velocity, and AF inducibility were evaluated weekly through atrial epicardial wires. After the protocol, atrial tissues were sampled for histological examination. The degree of reactive oxygen species expression was evaluated by dihydroethidium staining. The atrial effective refractory period reduction was smaller (P=0.06) and the degree of conduction velocity decrease was smaller in the pacing+CAN group compared with the pacing control group (P=0.009). The AF inducibility gradually increased in the pacing control group, but such an increase was suppressed in the pacing+CAN group (P=0.011). The pacing control group exhibited interstitial fibrosis and enhanced oxidative stress, which were suppressed in the pacing+CAN group. Conclusions CAN and possibly other SGLT2 inhibitors might be useful for preventing AF and suppressing the promotion of atrial remodeling as an AF substrate.
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Affiliation(s)
- Ryo Nishinarita
- Department of Cardiovascular Medicine Kitasato University School of Medicine Sagamihara Japan
| | - Shinichi Niwano
- Department of Cardiovascular Medicine Kitasato University School of Medicine Sagamihara Japan
| | - Hiroe Niwano
- Department of Education Tamagawa University, College of Education Machida Japan
| | - Hironori Nakamura
- Department of Cardiovascular Medicine Nerima Hikarigaoka Hospital Nerima Japan
| | - Daiki Saito
- Department of Cardiovascular Medicine Kitasato University School of Medicine Sagamihara Japan
| | - Tetsuro Sato
- Department of Cardiovascular Medicine Kitasato University School of Medicine Sagamihara Japan
| | - Gen Matsuura
- Department of Cardiovascular Medicine Kitasato University School of Medicine Sagamihara Japan
| | - Yuki Arakawa
- Department of Cardiovascular Medicine Kitasato University School of Medicine Sagamihara Japan
| | - Shuhei Kobayashi
- Department of Cardiovascular Medicine Kitasato University School of Medicine Sagamihara Japan
| | - Yuki Shirakawa
- Department of Cardiovascular Medicine Kitasato University School of Medicine Sagamihara Japan
| | - Ai Horiguchi
- Department of Cardiovascular Medicine Kitasato University School of Medicine Sagamihara Japan
| | - Naruya Ishizue
- Department of Cardiovascular Medicine Kitasato University School of Medicine Sagamihara Japan
| | - Tazuru Igarashi
- Department of Cardiovascular Medicine Kitasato University School of Medicine Sagamihara Japan
| | - Tomoharu Yoshizawa
- Department of Cardiovascular Medicine Yamato Municipal Hospital Yamato Japan
| | - Jun Oikawa
- Department of Cardiovascular Medicine Kitasato University School of Medicine Sagamihara Japan
| | - Yoshinobu Hara
- Department of Anatomy Kitasato University School of Medicine Sagamihara Japan
| | - Takafumi Katsumura
- Department of Anatomy Kitasato University School of Medicine Sagamihara Japan
| | - Jun Kishihara
- Department of Cardiovascular Medicine Kitasato University School of Medicine Sagamihara Japan
| | - Akira Satoh
- Department of Cardiovascular Medicine Yokohama Asahi Central Hospital Yokohama Japan
| | - Hidehira Fukaya
- Department of Cardiovascular Medicine Kitasato University School of Medicine Sagamihara Japan
| | - Hiroyuki Sakagami
- Department of Anatomy Kitasato University School of Medicine Sagamihara Japan
| | - Junya Ako
- Department of Cardiovascular Medicine Kitasato University School of Medicine Sagamihara Japan
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Li B, Yu Y, Liu K, Zhang Y, Geng Q, Zhang F, Li Y, Qi J. β-Hydroxybutyrate inhibits histone deacetylase 3 to promote claudin-5 generation and attenuate cardiac microvascular hyperpermeability in diabetes. Diabetologia 2021; 64:226-239. [PMID: 33106900 DOI: 10.1007/s00125-020-05305-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 09/07/2020] [Indexed: 02/07/2023]
Abstract
AIMS/HYPOTHESIS Microvascular endothelial hyperpermeability, mainly caused by claudin-5 deficiency, is the initial pathological change that occurs in diabetes-associated cardiovascular disease. The ketone body β-hydroxybutyrate (BHB) exerts unique beneficial effects on the cardiovascular system, but the involvement of BHB in promoting the generation of claudin-5 to attenuate cardiac microvascular hyperpermeability in diabetes is poorly understood. METHODS The effects of BHB on cardiac microvascular endothelial hyperpermeability and claudin-5 generation were evaluated in rats with streptozotocin-induced diabetes and in high glucose (HG)-stimulated human cardiac microvascular endothelial cells (HCMECs). To explore the underlying mechanisms, we also measured β-catenin nuclear translocation, binding of β-catenin, histone deacetylase (HDAC)1, HDAC3 and p300 to the Claudin-5 (also known as CLDN5) promoter, interaction between HDAC3 and β-catenin, and histone acetylation in the Claudin-5 promoter. RESULTS We found that 10 weeks of BHB treatment promoted claudin-5 generation and antagonised cardiac microvascular endothelial hyperpermeability in rat models of diabetes. Meanwhile, BHB promoted claudin-5 generation and inhibited paracellular permeability in HG-stimulated HCMECs. Specifically, BHB (2 mmol/l) inhibited HG-induced HDAC3 from binding to the Claudin-5 promoter, although nuclear translocation or promoter binding of β-catenin did not change with BHB treatment. In addition, BHB prevented the binding and co-localisation of HDAC3 to β-catenin in HG-stimulated HCMECs. Furthermore, using mass spectrometry, acetylated H3K14 (H3K14ac) in the Claudin-5 promoter following BHB treatment was identified, regardless of whether cells were stimulated by HG or not. Although reduced levels of acetylated H3K9 in the Claudin-5 promoter were found following HG stimulation, increased H3K14ac was specifically associated with BHB treatment. CONCLUSIONS/INTERPRETATION BHB inhibited HDAC3 and caused acetylation of H3K14 in the Claudin-5 promoter, thereby promoting claudin-5 generation and antagonising diabetes-associated cardiac microvascular hyperpermeability. Graphical abstract.
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Affiliation(s)
- Bin Li
- Department of Biochemistry, College of Integrated Chinese and Western Medicine, Hebei Medical University, Hebei, People's Republic of China
| | - Yijin Yu
- Department of Molecular Biology, Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, Hebei, People's Republic of China
| | - Kun Liu
- Department of Biochemistry, College of Integrated Chinese and Western Medicine, Hebei Medical University, Hebei, People's Republic of China
| | - Yuping Zhang
- Department of Molecular Biology, Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, Hebei, People's Republic of China
| | - Qi Geng
- Department of Molecular Biology, Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, Hebei, People's Republic of China
| | - Feng Zhang
- Department of Biochemistry, College of Integrated Chinese and Western Medicine, Hebei Medical University, Hebei, People's Republic of China
| | - Yanning Li
- Department of Biochemistry, College of Integrated Chinese and Western Medicine, Hebei Medical University, Hebei, People's Republic of China.
- Department of Molecular Biology, Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, Hebei, People's Republic of China.
| | - Jinsheng Qi
- Department of Biochemistry, College of Integrated Chinese and Western Medicine, Hebei Medical University, Hebei, People's Republic of China.
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Luo W, Yu Y, Wang H, Liu K, Wang Y, Huang M, Xuan C, Li Y, Qi J. Up-regulation of MMP-2 by histone H3K9 β-hydroxybutyrylation to antagonize glomerulosclerosis in diabetic rat. Acta Diabetol 2020; 57:1501-1509. [PMID: 32772200 DOI: 10.1007/s00592-020-01552-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 05/26/2020] [Indexed: 12/15/2022]
Abstract
AIMS Besides energy supply, β-hydroxybutyrate (BHB) acts as a bioactive molecule to play multiple protective roles, even in diabetes and its complications. The aim of this study was to investigate the antagonizing effects of BHB against diabetic glomerulosclerosis and the underlying mechanism. METHODS Male Sprague-Dawley rats were intraperitoneally injected with streptozotocin to induce diabetes and then treated with different concentrations of β-hydroxybutyrate. After 10 weeks, body weight, blood glucose, serum creatinine and 24-h urine protein were examined. Glomerular morphological changes and the contents of collagen type IV (COL IV) were evaluated. Then, transforming growth factor (TGF)-β/Smad3 contents and matrix metalloproteinase-2 (MMP-2) generation were detected. Moreover, the total contents of trans-activating histone H3K9 β-hydroxybutyrylation (H3K9bhb) and the contents of H3K9bhb in the Mmp-2 promoter were measured. RESULTS It was firstly confirmed that BHB treatments reduced renal biochemical indicators and attenuated glomerular morphological changes of the diabetic rats, with COL IV content decreased in a concentration-dependent manner. Then, BHB treatments were found to up-regulate renal MMP-2 generation of the diabetic rats significantly, while not affecting the increased TGF-β/Smad3 contents. Furthermore, the contents of H3K9bhb in the Mmp-2 promoter were elevated significantly for the middle and high concentrations of BHB treatments, up-regulating MMP-2 generation. CONCLUSION BHB treatments could up-regulate MMP-2 generation via causing elevated H3K9bhb in its promoter to antagonize glomerulosclerosis in the diabetic rats.
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Affiliation(s)
- Weigang Luo
- Department of Molecular Biology, Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, People's Republic of China
| | - Yijin Yu
- Department of Molecular Biology, Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, People's Republic of China
| | - Hao Wang
- Department of Biochemistry, College of Integrated Chinese and Western Medicine, Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Kun Liu
- Department of Biochemistry, College of Integrated Chinese and Western Medicine, Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Yu Wang
- Department of Molecular Biology, Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, People's Republic of China
| | - Minling Huang
- Department of Molecular Biology, Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, People's Republic of China
| | - Chenhao Xuan
- Department of Molecular Biology, Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, People's Republic of China
| | - Yanning Li
- Department of Molecular Biology, Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, People's Republic of China.
| | - Jinsheng Qi
- Department of Biochemistry, College of Integrated Chinese and Western Medicine, Hebei Medical University, Shijiazhuang, People's Republic of China.
- Department of Biochemistry, Hebei Key Laboratory of Medical Biotechnology, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, People's Republic of China.
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Gao L, Yuan P, Zhang Q, Fu Y, Hou Y, Wei Y, Zheng X, Feng W. Taxifolin improves disorders of glucose metabolism and water-salt metabolism in kidney via PI3K/AKT signaling pathway in metabolic syndrome rats. Life Sci 2020; 263:118713. [PMID: 33157091 DOI: 10.1016/j.lfs.2020.118713] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/23/2020] [Accepted: 11/02/2020] [Indexed: 12/16/2022]
Abstract
AIMS Our study was designed to explore the function and mechanism of taxifolin on glucose metabolism and water-salt metabolism in kidney with metabolic syndrome (MS) rats. MAIN METHODS Spontaneous hypertensive rats were induced by fructose to establish MS model. Systolic blood pressure (SBP) and homeostasis model assessment of insulin resistance (HOMA-IR) were measured after 7 weeks of continuous administration with taxifolin. Kidney injury indices and histopathological evaluation were done. The apoptosis rate of primary kidney cells was detected by flow cytometry. Insulin signaling pathway related proteins and renal glucose transport-related proteins were detected by western blotting. We assessed the effects of taxifolin on sodium water retention and renin-angiotensin-aldosterone system (RAAS) in MS rats. We examined not only changes in urine volume, osmotic pressure, urinary sodium and urinary chloride excretion, but also the effects on NA+/K+-ATPase and RAAS indicators. We also detected changes in inflammatory factors by immunohistochemical staining and immunofluorescence. In vitro experiment, high glucose and salt stimulated NRK-52E cells. By adding the PI3K inhibitor (wortmannin) to inhibit the PI3K, the effects of inhibiting the PI3K/AKT signaling pathway on glucose metabolism, water-sodium retention and inflammatory response were discussed. KEY FINDINGS Taxifolin effectively reversed SBP, HOMA-IR, the kidney indices and abnormal histopathological changes induced by MS. Besides, taxifolin called back the protein associated with the downstream glucose metabolism pathway of PI3K/AKT. It also inhibited overactivation of RAAS and inflammatory response. In vitro experiments have demonstrated that the PI3K/AKT signaling pathway plays an important role in this process. SIGNIFICANCE Taxifolin can improve homeostasis of glucose, inhibit overactivation of RAAS and reduce inflammatory response by PI3K/AKT signaling pathway.
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Affiliation(s)
- Liyuan Gao
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Peipei Yuan
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Qi Zhang
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Yang Fu
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Ying Hou
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Yaxin Wei
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Xiaoke Zheng
- Henan University of Chinese Medicine, Zhengzhou 450046, China; The Engineering and Technology Center for Chinese Medicine Development of Henan Province, Zhengzhou 450046, China.
| | - Weisheng Feng
- Henan University of Chinese Medicine, Zhengzhou 450046, China; The Engineering and Technology Center for Chinese Medicine Development of Henan Province, Zhengzhou 450046, China.
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Kalra S, Aydin H, Sahay M, Ghosh S, Ruder S, Tiwaskar M, Kilov G, Kishor K, Nair T, Makkar V, Unnikrishnan AG, Dhanda D, Gupta N, Srinivasan B, Kumar A. Cardiorenal Syndrome in Type 2 Diabetes Mellitus - Rational Use of Sodium-glucose Cotransporter-2 Inhibitors. EUROPEAN ENDOCRINOLOGY 2020; 16:113-121. [PMID: 33117442 DOI: 10.17925/ee.2020.16.2.113] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 07/01/2020] [Indexed: 01/10/2023]
Abstract
Cardiorenal syndrome (CRS) in people with type 2 diabetes mellitus (T2DM) illustrates the bidirectional link between the heart and the kidneys, with acute or chronic dysfunction of one organ adversely impacting the function of the other. Of the five subtypes identified, type 1 and 2 CRS occur because of the adverse impact of cardiac conditions on the kidneys. Type 3 and 4 occur when renal conditions affect the heart, and in type 5, systemic conditions impact the heart and kidneys concurrently. The cardiovascular and renoprotective benefits evidenced with sodium-glucose cotransporter-2 (SGLT2) inhibitors make them a potential choice in the management of CRS. Cardiovascular protection is mediated by a reduction in cardiac workload, blood pressure, and body weight; with improvement in lipid profile, uric acid levels, and adaptive ketogenesis process. Renoprotection is facilitated by reduction in albuminuria and hypoxic stress, and restoration of tubuloglomerular feedback. The favourable effect on cardiovascular complications and death, as well as renal complications and progression to end-stage kidney disease, has been confirmed in clinical trials. Guidelines endorse first-line use of SGLT2 inhibitors after metformin in patients with T2DM with high cardiovascular risk, chronic kidney disease or both. Since most trials with SGLT2 inhibitors excluded subjects with acute illness, patients with CRS subtypes 1 and 3 have not been studied adequately, making SGLT2 initiation in clinical practice challenging. Ongoing trials may provide evidence for SGLT2 inhibitor use in CRS. This review aims to enhance understanding of CRS and provide guidance for judicious use of SGLT2 inhibitors in T2DM.
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Affiliation(s)
- Sanjay Kalra
- Bharti Hospital and Bharti Research Institute of Diabetes and Endocrinology (BRIDE), Karnal, India
| | - Hasan Aydin
- Department of Endocrinology and Metabolism, Yeditepe University School of Medicine, Istanbul, Turkey
| | - Manisha Sahay
- Department of Nephrology, Osmania Medical College and General Hospital, Hyderabad, Telangana, India
| | | | - Sundeep Ruder
- Life Fourways Hospital, University of the Witwatersrand, Cape Town, South Africa
| | - Mangesh Tiwaskar
- Shilpa Medical Research Center, Dahisar East, Mumbai, Maharashtra, India
| | - Gary Kilov
- Department of General Practice, University of Melbourne, Melbourne, Australia
| | - Kamal Kishor
- Rama Superspeciality Hospital Karnal, Haryana, India
| | - Tiny Nair
- Department of Cardiology, PRS Hospital, Trivandrum, Kerala, India
| | - Vikas Makkar
- Dayanand Medical College and Hospital, Ludhiana, India
| | | | - Dinesh Dhanda
- Rama Superspeciality Hospital Karnal, Haryana, India
| | - Nikhil Gupta
- CanMed Multispeciality and Weight Management Clinics, Toronto, Canada
| | - Bharath Srinivasan
- Medical Affairs, AstraZeneca Pharma India Ltd, Bengaluru, Karnataka, India
| | - Amit Kumar
- Medical Affairs, AstraZeneca Pharma India Ltd, Bengaluru, Karnataka, India
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Vodošek Hojs N, Bevc S, Ekart R, Hojs R. Oxidative Stress Markers in Chronic Kidney Disease with Emphasis on Diabetic Nephropathy. Antioxidants (Basel) 2020; 9:925. [PMID: 32992565 PMCID: PMC7600946 DOI: 10.3390/antiox9100925] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/20/2020] [Accepted: 09/24/2020] [Indexed: 02/07/2023] Open
Abstract
Diabetes prevalence is increasing worldwide, especially through the increase of type 2 diabetes. Diabetic nephropathy occurs in up to 40% of diabetic patients and is the leading cause of end-stage renal disease. Various factors affect the development and progression of diabetic nephropathy. Hyperglycaemia increases free radical production, resulting in oxidative stress, which plays an important role in the pathogenesis of diabetic nephropathy. Free radicals have a short half-life and are difficult to measure. In contrast, oxidation products, including lipid peroxidation, protein oxidation, and nucleic acid oxidation, have longer lifetimes and are used to evaluate oxidative stress. In recent years, different oxidative stress biomarkers associated with diabetic nephropathy have been found. This review summarises current evidence of oxidative stress biomarkers in patients with diabetic nephropathy. Although some of them are promising, they cannot replace currently used clinical biomarkers (eGFR, proteinuria) in the development and progression of diabetic nephropathy.
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Affiliation(s)
- Nina Vodošek Hojs
- Department of Nephrology, Clinic for Internal Medicine, University Medical Centre Maribor, Ljubljanska 5, 2000 Maribor, Slovenia; (N.V.H.); (S.B.)
| | - Sebastjan Bevc
- Department of Nephrology, Clinic for Internal Medicine, University Medical Centre Maribor, Ljubljanska 5, 2000 Maribor, Slovenia; (N.V.H.); (S.B.)
- Faculty of Medicine, University of Maribor, Taborska 8, 2000 Maribor, Slovenia;
| | - Robert Ekart
- Faculty of Medicine, University of Maribor, Taborska 8, 2000 Maribor, Slovenia;
- Department of Dialysis, Clinic for Internal Medicine, University Medical Centre Maribor, Ljubljanska 5, 2000 Maribor, Slovenia
| | - Radovan Hojs
- Department of Nephrology, Clinic for Internal Medicine, University Medical Centre Maribor, Ljubljanska 5, 2000 Maribor, Slovenia; (N.V.H.); (S.B.)
- Faculty of Medicine, University of Maribor, Taborska 8, 2000 Maribor, Slovenia;
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Kuno A, Kimura Y, Mizuno M, Oshima H, Sato T, Moniwa N, Tanaka M, Yano T, Tanno M, Miki T, Miura T. Empagliflozin attenuates acute kidney injury after myocardial infarction in diabetic rats. Sci Rep 2020; 10:7238. [PMID: 32350374 PMCID: PMC7190820 DOI: 10.1038/s41598-020-64380-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 04/15/2020] [Indexed: 12/19/2022] Open
Abstract
Acute kidney injury (AKI) predicts poor prognosis in patients with acute myocardial infarction (MI) and diabetes mellitus (DM) is an independent risk factor of AKI. Recent clinical studies have shown the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on cardiovascular and renal outcomes in patients with DM. We recently reported that canagliflozin normalized susceptibility of diabetic rats to AKI after acute MI via β-hydroxybutyrate-mediated suppression of NOX expression. Here we examined whether the same renoprotective effect is shared by empagliflozin. Serum creatinine levels were not changed by MI induced by coronary artery occlusion in LETO, non-diabetic control rats, and OLETF, obese type 2 diabetic rats. However, immunohistochemistry revealed that MI increased renal expression of NGAL and KIM-1, early markers of tubular injury, by 3.2-fold and 2.6-fold, respectively, in OLETF. These increases in injury markers were not observed in LETO. Pretreatment with empagliflozin of OLETF for 2 weeks improved hyperglycemia, increased blood β-hydroxybutyrate level, and suppressed MI-induced expression of NGAL and KIM-1. Empagliflozin suppressed upregulation of NOX2 and NOX4 in the kidney of OLETF. Taken together with the results of our previous study, it was concluded that treatment with the SGLT2 inhibitor protects the diabetic kidney from MI-induced AKI.
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Affiliation(s)
- Atsushi Kuno
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan. .,Department of Pharmacology, Sapporo Medical University School of Medicine, Sapporo, Japan.
| | - Yukishige Kimura
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masashi Mizuno
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiroto Oshima
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tatsuya Sato
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Cellular Physiology and Signal Transduction, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Norihito Moniwa
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Marenao Tanaka
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Toshiyuki Yano
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masaya Tanno
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takayuki Miki
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tetsuji Miura
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
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Song Z, Zhu J, Wei Q, Dong G, Dong Z. Canagliflozin reduces cisplatin uptake and activates Akt to protect against cisplatin-induced nephrotoxicity. Am J Physiol Renal Physiol 2020; 318:F1041-F1052. [PMID: 32150448 DOI: 10.1152/ajprenal.00512.2019] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Cisplatin is a widely used chemotherapy drug with notorious nephrotoxicity. Na+-glucose cotransporter 2 inhibitors are a class of novel antidiabetic agents that may have other effects in the kidneys besides blood glucose control. In the present study, we demonstrated that canagliflozin significantly attenuates cisplatin-induced nephropathy in C57BL/6 mice and suppresses cisplatin induced renal proximal tubular cell apoptosis in vitro. The protective effect of canagliflozin was associated with inhibition of p53, p38 and JNK activation. Mechanistically, canagliflozin partially reduced cisplatin uptake by kidney tissues in mice and renal tubular cells in culture. In addition, canagliflozin enhanced the activation of Akt and inhibited the mitochondrial pathway of apoptosis during cisplatin treatment. The protective effect of canagliflozin was diminished by the phosphatidylinositol 3-kinase/Akt inhibitor LY294002. Notably, canagliflozin did not affect the chemotherapeutic efficacy of cisplatin in A549 and HCT116 cancer cell lines. These results suggest a new application of canagliflozin for renoprotection in cisplatin chemotherapy. Canagliflozin may protect kidneys by reducing cisplatin uptake and activating cell survival pathways.
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Affiliation(s)
- Zhixia Song
- Department of Nephrology, Central People's Hospital of Yichang, The First Clinical Medical College of Three Gorges University, Yichang, China.,Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia.,Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia
| | - Jiefu Zhu
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia.,Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia.,Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Qingqing Wei
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia.,Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia
| | - Guie Dong
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia.,Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia
| | - Zheng Dong
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia.,Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia
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Shao Q, Meng L, Lee S, Tse G, Gong M, Zhang Z, Zhao J, Zhao Y, Li G, Liu T. Empagliflozin, a sodium glucose co-transporter-2 inhibitor, alleviates atrial remodeling and improves mitochondrial function in high-fat diet/streptozotocin-induced diabetic rats. Cardiovasc Diabetol 2019; 18:165. [PMID: 31779619 PMCID: PMC6882319 DOI: 10.1186/s12933-019-0964-4] [Citation(s) in RCA: 212] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 11/10/2019] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Diabetes mellitus is an important risk factor for atrial fibrillation (AF) development. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are used for the treatment of type 2 diabetes mellitus (T2DM). Their cardioprotective effects have been reported but whether they prevent AF in T2DM patients are less well-explored. We tested the hypothesis that the SGLT-2 inhibitor, empagliflozin, can prevent atrial remodeling in a diabetic rat model. METHODS High-fat diet and low-dose streptozotocin (STZ) treatment were used to induce T2DM. A total of 96 rats were randomized into the following four groups: (i) control (ii) T2DM, (iii) low-dose empagliflozin (10 mg/kg/day)/T2DM; and (iv) high-dose empagliflozin (30 mg/kg/day)/T2DM by the intragastric route for 8 weeks. RESULTS Compared with the control group, left atrial diameter, interstitial fibrosis and the incidence of AF inducibility were significantly increased in the DM group. Moreover, atrial mitochondrial respiratory function, mitochondrial membrane potential, and mitochondrial biogenesis were impaired. Empagliflozin treatment significantly prevented the development of these abnormalities in DM rats, likely via the peroxisome proliferator-activated receptor-c coactivator 1α (PGC-1α)/nuclear respiratory factor-1 (NRF-1)/mitochondrial transcription factor A (Tfam) signaling pathway. CONCLUSIONS Empagliflozin can ameliorate atrial structural and electrical remodeling as well as improve mitochondrial function and mitochondrial biogenesis in T2DM, hence may be potentially used in the prevention of T2DM-related atrial fibrillation.
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MESH Headings
- Animals
- Atrial Fibrillation/etiology
- Atrial Fibrillation/metabolism
- Atrial Fibrillation/physiopathology
- Atrial Fibrillation/prevention & control
- Atrial Function, Left/drug effects
- Atrial Remodeling/drug effects
- Benzhydryl Compounds/pharmacology
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Experimental/etiology
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Experimental/physiopathology
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/etiology
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/physiopathology
- Diet, High-Fat
- Disease Models, Animal
- Glucosides/pharmacology
- Heart Rate/drug effects
- Male
- Membrane Potential, Mitochondrial/drug effects
- Mitochondria, Heart/drug effects
- Mitochondria, Heart/metabolism
- Mitochondrial Proteins/metabolism
- Organelle Biogenesis
- Oxidative Stress/drug effects
- Rats, Sprague-Dawley
- Signal Transduction
- Sodium-Glucose Transporter 2 Inhibitors/pharmacology
- Streptozocin
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Affiliation(s)
- Qingmiao Shao
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, 300211, People's Republic of China
| | - Lei Meng
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, 300211, People's Republic of China
| | - Sharen Lee
- Laboratory of Cardiovascular Physiology, Li Ka Shing Institute of Health Sciences, Sha Tin, Hong Kong S.A.R., China
| | - Gary Tse
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, 300211, People's Republic of China
| | - Mengqi Gong
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, 300211, People's Republic of China
| | - Zhiwei Zhang
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, 300211, People's Republic of China
| | - Jichao Zhao
- Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand
| | - Yungang Zhao
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Department of Health & Exercise Science, Tianjin University of Sport, Tianjin, 300381, People's Republic of China
| | - Guangping Li
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, 300211, People's Republic of China.
| | - Tong Liu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, 300211, People's Republic of China.
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Duni A, Liakopoulos V, Roumeliotis S, Peschos D, Dounousi E. Oxidative Stress in the Pathogenesis and Evolution of Chronic Kidney Disease: Untangling Ariadne's Thread. Int J Mol Sci 2019; 20:ijms20153711. [PMID: 31362427 PMCID: PMC6695865 DOI: 10.3390/ijms20153711] [Citation(s) in RCA: 222] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 07/26/2019] [Accepted: 07/26/2019] [Indexed: 02/07/2023] Open
Abstract
Amplification of oxidative stress is present since the early stages of chronic kidney disease (CKD), holding a key position in the pathogenesis of renal failure. Induction of renal pro-oxidant enzymes with excess generation of reactive oxygen species (ROS) and accumulation of dityrosine-containing protein products produced during oxidative stress (advanced oxidation protein products—AOPPs) have been directly linked to podocyte damage, proteinuria, and the development of focal segmental glomerulosclerosis (FSGS) as well as tubulointerstitial fibrosis. Vascular oxidative stress is considered to play a critical role in CKD progression, and ROS are potential mediators of the impaired myogenic responses of afferent renal arterioles in CKD and impaired renal autoregulation. Both oxidative stress and inflammation are CKD hallmarks. Oxidative stress promotes inflammation via formation of proinflammatory oxidized lipids or AOPPs, whereas activation of nuclear factor κB transcription factor in the pro-oxidant milieu promotes the expression of proinflammatory cytokines and recruitment of proinflammatory cells. Accumulating evidence implicates oxidative stress in various clinical models of CKD, including diabetic nephropathy, IgA nephropathy, polycystic kidney disease as well as the cardiorenal syndrome. The scope of this review is to tackle the issue of oxidative stress in CKD in a holistic manner so as to provide a future framework for potential interventions.
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Affiliation(s)
- Anila Duni
- Department of Nephrology, Medical School, University of Ioannina, 45110 Ioannina, Greece
| | - Vassilios Liakopoulos
- Division of Nephrology and Hypertension, 1st Department of Internal Medicine, AHEPA Hospital, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Stefanos Roumeliotis
- Division of Nephrology and Hypertension, 1st Department of Internal Medicine, AHEPA Hospital, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Dimitrios Peschos
- Laboratory of Physiology, Medical School, University of Ioannina, 45110 Ioannina, Greece
| | - Evangelia Dounousi
- Department of Nephrology, Medical School, University of Ioannina, 45110 Ioannina, Greece.
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