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Rosas-Martínez L, Rodríguez-Muñoz R, Namorado-Tonix MDC, Missirlis F, Del Valle-Mondragón L, Sánchez-Mendoza A, Reyes-Sánchez JL, Cervantes-Pérez LG. Peroxisome Proliferator-Activated Receptor Alpha Stimulation Preserves Renal Tight Junction Components in a Rat Model of Early-Stage Diabetic Nephropathy. Int J Mol Sci 2024; 25:13152. [PMID: 39684861 DOI: 10.3390/ijms252313152] [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: 10/29/2024] [Revised: 12/02/2024] [Accepted: 12/04/2024] [Indexed: 12/18/2024] Open
Abstract
Chronic hyperglycemia results in morphological and functional alterations of the kidney and microvascular damage, leading to diabetic nephropathy (DN). Since DN progresses to irreversible renal damage, it is important to elucidate a pharmacological strategy aimed for treating DN in the early stage. Here, we used the type 2 diabetic rat model to induce DN and show a nephroprotective effect following the stimulation of PPAR-α, which stabilized renal tight junction components claudin-2, claudin-5, and claudin-16. At 14 weeks old, streptozotocin-induced DN, evidenced by elevated creatinine clearance, proteinuria, and electrolyte excretion, was followed by an elevation in oxidative stress and increasing MMP activities affecting the integrity of claudin-2 and claudin-5. Treatment with a PPAR-α agonists decreased glucose levels in diabetic rats. In addition, we found that the expressions of CLDN-5 in glomeruli, CLDN-2 in proximal tubules, and CLDN-16 in the thick ascending limb of the loop of Henle were increased after treatment. As a result, renal function improved, while the oxidative stress and enzymatic activity of MMP-2 and MMP-9 decreased. In conclusion, PPAR-α stimulation prevented the decrease in claudins through a mechanism involving a correction of hyperglycemia, decreasing it in kidney oxidative stress and MMP-2 and MMP-9 activities, showing a promising nephroprotective action in the early stage of DN.
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Affiliation(s)
- Lorena Rosas-Martínez
- Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Juan Badiano No. 1, Col. Seccion XVI, Tlalpan, Mexico City 14080, Mexico
- Department of Physiology, Biophysics, and Neuroscience, Center for Research and Advanced Studies of National Polytechnic Institute, CINVESTAV-IPN, Instituto Politécnico Nacional 2508, San Pedro Zacatenco, Gustavo A. Madero, Mexico City 07360, Mexico
| | - Rafael Rodríguez-Muñoz
- Department of Physiology, Biophysics, and Neuroscience, Center for Research and Advanced Studies of National Polytechnic Institute, CINVESTAV-IPN, Instituto Politécnico Nacional 2508, San Pedro Zacatenco, Gustavo A. Madero, Mexico City 07360, Mexico
| | - María Del Carmen Namorado-Tonix
- Department of Physiology, Biophysics, and Neuroscience, Center for Research and Advanced Studies of National Polytechnic Institute, CINVESTAV-IPN, Instituto Politécnico Nacional 2508, San Pedro Zacatenco, Gustavo A. Madero, Mexico City 07360, Mexico
| | - Fanis Missirlis
- Department of Physiology, Biophysics, and Neuroscience, Center for Research and Advanced Studies of National Polytechnic Institute, CINVESTAV-IPN, Instituto Politécnico Nacional 2508, San Pedro Zacatenco, Gustavo A. Madero, Mexico City 07360, Mexico
| | - Leonardo Del Valle-Mondragón
- Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Juan Badiano No. 1, Col. Seccion XVI, Tlalpan, Mexico City 14080, Mexico
| | - Alicia Sánchez-Mendoza
- Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Juan Badiano No. 1, Col. Seccion XVI, Tlalpan, Mexico City 14080, Mexico
| | - José L Reyes-Sánchez
- Department of Physiology, Biophysics, and Neuroscience, Center for Research and Advanced Studies of National Polytechnic Institute, CINVESTAV-IPN, Instituto Politécnico Nacional 2508, San Pedro Zacatenco, Gustavo A. Madero, Mexico City 07360, Mexico
| | - Luz Graciela Cervantes-Pérez
- Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Juan Badiano No. 1, Col. Seccion XVI, Tlalpan, Mexico City 14080, Mexico
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Hsu YC, Shih YH, Ho C, Liu CC, Liaw CC, Lin HY, Lin CL. Ethyl Acetate Fractions of Salvia miltiorrhiza Bunge (Danshen) Crude Extract Modulate Fibrotic Signals to Ameliorate Diabetic Kidney Injury. Int J Mol Sci 2024; 25:8986. [PMID: 39201671 PMCID: PMC11354680 DOI: 10.3390/ijms25168986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 07/30/2024] [Accepted: 08/08/2024] [Indexed: 09/03/2024] Open
Abstract
Diabetic nephropathy, a leading cause of end-stage renal disease, accounts for significant morbidity and mortality. It is characterized by microinflammation in the glomeruli and myofibroblast activation in the tubulointerstitium. Salvia miltiorrhiza Bunge, a traditional Chinese medicine, is shown to possess anti-inflammatory and anti-fibrotic properties, implying its renal-protective potential. This study investigates which type of component can reduce the damage caused by diabetic nephropathy in a single setting. The ethyl acetate (EtOAc) layer was demonstrated to provoke peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ activities in renal mesangial cells by dual luciferase reporter assay. In a high glucose (HG)-cultured mesangial cell model, the EtOAc layer substantially inhibited HG-induced elevations of interleukin-1β, transforming growth factor-β1 (TGF-β1), and fibronectin, whereas down-regulated PPAR-γ was restored. In addition, among the extracts of S. miltiorrhiza, the EtOAc layer effectively mitigated TGF-β1-stimulated myofibroblast activation. The EtOAc layer also showed a potent ability to attenuate renal hypertrophy, proteinuria, and fibrotic severity by repressing diabetes-induced proinflammatory factor, extracellular matrix accumulation, and PPAR-γ reduction in the STZ-induced diabetes mouse model. Our findings, both in vitro and in vivo, indicate the potential of the EtOAc layer from S. miltiorrhiza for future drug development targeting diabetic nephropathy.
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Affiliation(s)
- Yung-Chien Hsu
- Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan; (Y.-C.H.); (Y.-H.S.); (C.-C.L.)
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 61363, Taiwan;
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 333423, Taiwan
| | - Ya-Hsueh Shih
- Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan; (Y.-C.H.); (Y.-H.S.); (C.-C.L.)
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 61363, Taiwan;
| | - Cheng Ho
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 61363, Taiwan;
- Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan
| | - Cheng-Chi Liu
- Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan; (Y.-C.H.); (Y.-H.S.); (C.-C.L.)
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 61363, Taiwan;
| | - Chia-Ching Liaw
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 112304, Taiwan;
| | - Hui-Yi Lin
- School of Pharmacy, China Medical University, Taichung 406040, Taiwan
| | - Chun-Liang Lin
- Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan; (Y.-C.H.); (Y.-H.S.); (C.-C.L.)
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 61363, Taiwan;
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Kidney Research Center, Chang Gung Memorial Hospital, Taipei 10507, Taiwan
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
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Comella F, Lama A, Pirozzi C, Annunziata C, Piegari G, Sodano F, Melini S, Paciello O, Lago Paz F, Meli R, Mattace Raso G. Oleoylethanolamide attenuates acute-to-chronic kidney injury: in vivo and in vitro evidence of PPAR-α involvement. Biomed Pharmacother 2024; 171:116094. [PMID: 38183745 DOI: 10.1016/j.biopha.2023.116094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 12/22/2023] [Accepted: 12/26/2023] [Indexed: 01/08/2024] Open
Abstract
Chronic kidney disease (CKD) development after acute kidney injury (AKI) involves multiple mechanisms, including inflammation, epithelial-mesenchymal transition (EMT), and extracellular matrix deposition, leading to progressive tubulointerstitial fibrosis. Recently, a central role for peroxisome-proliferator activated receptor (PPAR)-α has been addressed in preserving kidney function during AKI. Among endogenous lipid mediators, oleoylethanolamide (OEA), a PPAR-α agonist, has been studied for its metabolic and anti-inflammatory effects. Here, we have investigated OEA effects on folic acid (FA)-induced kidney injury in mice and the underlying mechanisms. OEA improved kidney function, normalized urine output, and reduced serum BUN, creatinine, and albuminuria. Moreover, OEA attenuated tubular epithelial injury, as shown by histological analysis, and decreased expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1. Gene expression analysis of kidney tissue indicated that OEA limited immune cell infiltration and inflammation. Moreover, OEA significantly inhibited Wnt7b and Catnb1 gene transcription and α-smooth muscle actin expression, indicating suppression of EMT. Accordingly, OEA exhibited an anti-fibrotic effect, as shown by Masson staining and the reduced levels of transforming growth factor (TGF)-β1, fibronectin, and collagen IV. Mechanistically, the nephroprotective effect of OEA was related to PPAR-α activation since OEA failed to exert its beneficial activity in FA-insulted PPAR-α-/- mice. PPAR-α involvement was also confirmed in HK2 cells where GW6471, a PPAR-α antagonist, blunted OEA activity on the TGF-β1 signalling pathway and associated pro-inflammatory and fibrotic patterns. Our findings revealed that OEA counteracts kidney injury by controlling inflammation and fibrosis, making it an effective therapeutic tool for limiting AKI to CKD progression.
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Affiliation(s)
- Federica Comella
- Department of Pharmacy, School of Medicine, University of Naples "Federico II, 80131 Naples, Italy
| | - Adriano Lama
- Department of Pharmacy, School of Medicine, University of Naples "Federico II, 80131 Naples, Italy
| | - Claudio Pirozzi
- Department of Pharmacy, School of Medicine, University of Naples "Federico II, 80131 Naples, Italy
| | - Chiara Annunziata
- Department of Pharmacy, School of Medicine, University of Naples "Federico II, 80131 Naples, Italy
| | - Giuseppe Piegari
- Department of Veterinary Medicine and Animal Production, University of Naples "Federico II", 80137 Naples, Italy
| | - Federica Sodano
- Department of Pharmacy, School of Medicine, University of Naples "Federico II, 80131 Naples, Italy
| | - Stefania Melini
- Department of Pharmacy, School of Medicine, University of Naples "Federico II, 80131 Naples, Italy
| | - Orlando Paciello
- Department of Veterinary Medicine and Animal Production, University of Naples "Federico II", 80137 Naples, Italy
| | - Francisca Lago Paz
- University Clinic Hospital of Santiago de Compostela, Santiago de Compostela 15706, Spain
| | - Rosaria Meli
- Department of Pharmacy, School of Medicine, University of Naples "Federico II, 80131 Naples, Italy
| | - Giuseppina Mattace Raso
- Department of Pharmacy, School of Medicine, University of Naples "Federico II, 80131 Naples, Italy.
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Jiang Y, Li Z, Yue R, Liu G, Yang M, Long C, Yan D. Evidential support for garlic supplements against diabetic kidney disease: a preclinical meta-analysis and systematic review. Food Funct 2024; 15:12-36. [PMID: 38051214 DOI: 10.1039/d3fo02407e] [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: 12/07/2023]
Abstract
Garlic (Allium sativum L.) is a popular spice that is widely used for food and medicinal purposes and has shown potential effects on diabetic kidney disease (DKD). Nevertheless, systematic preclinical studies are still lacking. In this meta-analysis and systematic review, we evaluated the role and potential mechanisms of action of garlic and its derived components in animal models of DKD. We searched eight databases for relevant studies from the establishment of the databases to December 2022 and updated in April 2023 before the completion of this review. A total of 24 trials were included in the meta-analysis. It provided preliminary evidence that supplementing with garlic could improve the indicators of renal function (BUN, Scr, 24 h urine volume, proteinuria, and KI) and metabolic disorders (BG, insulin, and body weight). Meanwhile, the beneficial effects of garlic and its components in DKD could be related to alleviating oxidative stress, suppressing inflammatory reactions, delaying renal fibrosis, and improving glucose metabolism. Furthermore, time-dose interval analysis exhibited relatively greater effectiveness when garlic products were supplied at doses of 500 mg kg-1 with interventions lasting 8-10 weeks, and garlic components were administered at doses of 45-150 mg kg-1 with interventions lasting 4-10 weeks. This meta-analysis and systematic review highlights for the first time the therapeutic potential of garlic supplementation in animal models of DKD and offers a more thorough evaluation of its effects and mechanisms to establish an evidence-based basis for designing future clinical trials.
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Affiliation(s)
- Yayi Jiang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
| | - Zihan Li
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
| | - Rensong Yue
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
| | - Guojie Liu
- School of Chemical Engineering, Sichuan University, Chengdu, China
| | - Maoyi Yang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
| | - Caiyi Long
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
| | - Dawei Yan
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
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Wang CH, Surbhi, Goraya S, Byun J, Pennathur S. Fatty acids and inflammatory stimuli induce expression of long-chain acyl-CoA synthetase 1 to promote lipid remodeling in diabetic kidney disease. J Biol Chem 2024; 300:105502. [PMID: 38016515 PMCID: PMC10770716 DOI: 10.1016/j.jbc.2023.105502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 10/30/2023] [Accepted: 11/10/2023] [Indexed: 11/30/2023] Open
Abstract
Fatty acid handling and complex lipid synthesis are altered in the kidney cortex of diabetic patients. We recently showed that inhibition of the renin-angiotensin system without changes in glycemia can reverse diabetic kidney disease (DKD) and restore the lipid metabolic network in the kidney cortex of diabetic (db/db) mice, raising the possibility that lipid remodeling may play a central role in DKD. However, the roles of specific enzymes involved in lipid remodeling in DKD have not been elucidated. In the present study, we used this diabetic mouse model and a proximal tubule epithelial cell line (HK2) to investigate the potential relationship between long-chain acyl-CoA synthetase 1 (ACSL1) and lipid metabolism in response to fatty acid exposure and inflammatory signals. We found ACSL1 expression was significantly increased in the kidney cortex of db/db mice, and exposure to palmitate or tumor necrosis factor-α significantly increased Acsl1 mRNA expression in HK-2 cells. In addition, palmitate treatment significantly increased the levels of long-chain acylcarnitines and fatty acyl CoAs in HK2 cells, and these increases were abolished in HK2 cell lines with specific deletion of Acsl1(Acsl1KO cells), suggesting a key role for ACSL1 in fatty acid β-oxidation. In contrast, tumor necrosis factor-α treatment significantly increased the levels of short-chain acylcarnitines and long-chain fatty acyl CoAs in HK2 cells but not in Acsl1KO cells, consistent with fatty acid channeling to complex lipids. Taken together, our data demonstrate a key role for ACSL1 in regulating lipid metabolism, fatty acid partitioning, and inflammation.
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Affiliation(s)
- Chih-Hong Wang
- Department of Physiology, Tulane University of School Medicine, New Orleans, Louisiana, USA; Tulane Hypertension & Renal Center of Excellence, Tulane University, New Orleans, Louisiana, USA; Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Surbhi
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Sayhaan Goraya
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Jaeman Byun
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Subramaniam Pennathur
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
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Ali AA, Saad EB, El-Rhman RHA, El-Raouf OMA, Gad AM. Impact of peroxisome proliferator activated receptor agonist drugs in a model of nephrotoxicity in rats. J Biochem Mol Toxicol 2023; 37:e23350. [PMID: 36988379 DOI: 10.1002/jbt.23350] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 01/19/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023]
Abstract
Doxorubicin (DOX) is one of the basic anticancer drugs, nonetheless its use is restricted due to noxious side effects. Kidney failure is one of the main side effects that restrict its medical use. The current study assessed the nephroprotective effects of fenofibrate and pioglitazone against the renal injury induced by doxorubicin in rats and illustrated the probable mechanisms underlying these protective effects. For this purpose, Male Sprague-Dawley rats weighing (200-230 g) were allocated into seven groups treated for 15 days as following: control (50% corn oil + 50% DMSO p.o), fenofibrate (100 mg/kg p.o) and pioglitazone (10 mg/kg p.o) as well as four groups of DOX (15 mg/kg i.p on 11th day). DOX groups included DOX alone and DOX with protective drugs fenofibrate, pioglitazone or both of them. As a result of doxorubicin nephrotoxicity; serum creatinine and blood urea nitrogen were remarkably elevated. Moreover, renal glutathione was significantly reduced while tissue lipid peroxidation malondialdehyde, tumor necrosis factor-α, nuclear factor-kappa B p65 (NF-κB p65), interleukin-1β, p38 mitogen activated protein kinase (p38-MAPK) and caspase-3 (Casp-3) were significantly augmented. Treatment with fenofibrate and pioglitazone either alone or in combination markedly attenuated DOX-induced injury by suppression of oxidative stress, inflammation and apoptosis. The above-mentioned biochemical markers were affirmed by histological assessment. In conclusion, fenofibrate, pioglitazone, and their combination possess potential prophylactic effects against doxorubicin-induced renal injury through modulation of p38-MAPK/NF-κB p65 pathway with superiority to the combination.
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Affiliation(s)
- Azza A Ali
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Eman B Saad
- The Department of Pharmacology, Egyptian Drug Authority, EDA, Formerly NODCAR, Giza, Egypt
| | - Rana H Abd El-Rhman
- The Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University-Kantara Branch, Ismailia, Egypt
| | - Ola M Abd El-Raouf
- The Department of Pharmacology, Egyptian Drug Authority, EDA, Formerly NODCAR, Giza, Egypt
| | - Amany M Gad
- The Department of Pharmacology, Egyptian Drug Authority, EDA, Formerly NODCAR, Giza, Egypt
- The Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University-Kantara Branch, Ismailia, Egypt
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Balakumar P, Venkatesan K, Abdulla Khan N, Raghavendra NM, Venugopal V, Bharathi DR, Fuloria NK. Mechanistic insights into the beneficial effects of curcumin on insulin resistance: opportunities and challenges. Drug Discov Today 2023:103627. [PMID: 37224995 DOI: 10.1016/j.drudis.2023.103627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 05/03/2023] [Accepted: 05/17/2023] [Indexed: 05/26/2023]
Abstract
The past couple of decades in particular have seen a rapid increase in the prevalence of type 2 diabetes mellitus (T2DM), a debilitating metabolic disorder characterised by insulin resistance. The insufficient efficacy of current management strategies for insulin resistance calls for additional therapeutic options. The preponderance of evidence suggests potential beneficial effects of curcumin on insulin resistance, while modern science provides a scientific basis for its potential applications against the disease. Curcumin combats insulin resistance by increasing the levels of circulating irisin and adiponectin, activating PPARγ, suppressing Notch1 signalling, and regulating SREBP target genes, among others. In this review, we bring together the diverse areas pertaining to our current understanding of the potential benefits of curcumin on insulin resistance, associated mechanistic insights, and new therapeutic possibilities. Teaser: Current approaches to manage insulin resistance are not highly efficacious, which necessitates additional therapeutic options; curcumin combats insulin resistance by improving the levels of circulating irisin and adiponectin, upregulating and activating PPARγ, and suppressing Notch‑1 signalling.
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Affiliation(s)
- Pitchai Balakumar
- The Office of Research and Development, Periyar Maniammai Institute of Science & Technology, Vallam, Thanjavur 613 403, Tamil Nadu, India.
| | - Kumar Venkatesan
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Al-Qara, Abha 61421, Saudi Arabia
| | - Noohu Abdulla Khan
- Department of Clinical Pharmacy, College of Pharmacy, King Khalid University, Al-Qara, Abha 61421, Saudi Arabia
| | - N M Raghavendra
- Department of Pharmaceutical Chemistry, College of Pharmaceutical Sciences, Dayananda Sagar University, Bengaluru 560 111, India
| | - Vijayan Venugopal
- School of Pharmacy, Sri Balaji Vidyapeeth Deemed-to-be University, Puducherry 607 402, India
| | - D R Bharathi
- Department of Pharmacology, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, B G Nagara, Nagamangala 571 448, India
| | - Neeraj K Fuloria
- Pharmaceutical Chemistry Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia
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MORG1—A Negative Modulator of Renal Lipid Metabolism in Murine Diabetes. Biomedicines 2021; 10:biomedicines10010030. [PMID: 35052710 PMCID: PMC8772719 DOI: 10.3390/biomedicines10010030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 12/17/2021] [Accepted: 12/21/2021] [Indexed: 12/19/2022] Open
Abstract
Renal fatty acid (FA) metabolism is severely altered in type 1 and 2 diabetes mellitus (T1DM and T2DM). Increasing evidence suggests that altered lipid metabolism is linked to tubulointerstitial fibrosis (TIF). Our previous work has demonstrated that mice with reduced MORG1 expression, a scaffold protein in HIF and ERK signaling, are protected against TIF in the db/db mouse model. Renal TGF-ß1 expression and EMT-like changes were reduced in mice with single-allele deficiency of MORG1. Given the well-known role of HIF and ERK signaling in metabolic regulation, here we examined whether protection was also associated with a restoration of lipid metabolism. Despite similar features of TIF in T1DM and T2DM, diabetes-associated changes in renal lipid metabolism differ between both diseases. We found that de novo synthesis of FA/cholesterol and β-oxidation were more strongly disrupted in T1DM, whereas pathological fat uptake into tubular cells mediates lipotoxicity in T2DM. Thus, diminished MORG1 expression exerts renoprotection in the diabetic nephropathy by modulating important factors of TIF and lipid dysregulation to a variable extent in T1DM and T2DM. Prospectively, targeting MORG1 appears to be a promising strategy to reduce lipid metabolic alterations in diabetic nephropathy.
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9
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An W, Huang Y, Chen S, Teng T, Liu J, Xu Y. Efficacy and safety of Huangkui capsule for diabetic nephropathy: A protocol for systematic review and meta-analysis. Medicine (Baltimore) 2021; 100:e27569. [PMID: 34678897 PMCID: PMC8542127 DOI: 10.1097/md.0000000000027569] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 10/05/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is 1 of the most serious complications of diabetes mellitus and the leading cause of end-stage renal disease in the world. Huangkui capsule, extracted from Abelmoschus manihot (L.) medic (AM), has been widely used to treat DN. However, there is no consensus on the efficacy of Huangkui capsule for DN. This study aims to perform meta-analysis to systematically review the efficacy and safety of Huangkui capsule. METHODS The following 9 electronic databases will be comprehensively searched: PubMed, web of science, MEDLINE, Embase, Cochrane Library, China National Knowledge Infrastructure, Chinese Scientific Journals Database, Wanfang data, and Chinese BioMedicine Literature Database. The retrieval time is from their inception to May 2021. According to the inclusion and exclusion criteria, 2 reviewers independently completed the study selection, data extraction, risk of bias assessment, and data synthesis. Review Manager Version 5.3 software will be used to conduct meta-analysis. RESULTS This study provides a high-quality synthesis to assess the efficacy of Huangkui capsule for treating diabetic nephropathy. CONCLUSION The result of this systematic review will provide objective evidence-based basis to judge the effectiveness and safety of Huangkui capsule on diabetic nephropathy.
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Affiliation(s)
- Wenrong An
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yanqin Huang
- Department of Endocrine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Shouqiang Chen
- Department of Endocrine, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Tao Teng
- Department of Endocrine, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Juan Liu
- Shandong Rehabilitation Research Center, Jinan, China
| | - Yunsheng Xu
- Department of Endocrine, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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10
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Kim MJ, Kim DH, Bang E, Noh SG, Chun P, Yokozawa T, Moon HR, Chung HY. PPARα Agonist, MHY3200, Alleviates Renal Inflammation during Aging via Regulating ROS/Akt/FoxO1 Signaling. Molecules 2021; 26:3197. [PMID: 34073584 PMCID: PMC8198004 DOI: 10.3390/molecules26113197] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/11/2021] [Accepted: 05/14/2021] [Indexed: 12/01/2022] Open
Abstract
PPARα is a ligand-dependent transcription factor and its activation is known to play an important role in cell defense through anti-inflammatory and antioxidant effects. MHY3200 (2-[4-(5-chlorobenzo[d]thiazol-2-yl)phenoxy]-2,2-difluoroacetic acid), a novel benzothiazole-derived peroxisome proliferator-activated receptor α (PPARα) agonist, is a synthesized PPARα activator. This study examined the beneficial effects of MHY3200 on age-associated alterations in reactive oxygen species (ROS)/Akt/forkhead box (FoxO) 1 signaling in rat kidneys. Young (7-month-old) and old (22-month-old) rats were treated with MHY3200 (1 mg/kg body weight/day or 3 mg/kg body weight/day) for two weeks. MHY3200 treatment led to a notable decrease in triglyceride and insulin levels in serum from old rats. The elevated kidney ROS level, serum insulin level, and Akt phosphorylation in old rats were reduced following MHY3200 treatment; moreover, FoxO1 phosphorylation increased. MHY3200 treatment led to the increased level of FoxO1 and its target gene, MnSOD. MHY3200 suppressed cyclooxygenase-2 expression by activating PPARα and inhibiting the activation of nuclear factor-κB (NF-κB) in the kidneys of old rats. Our results suggest that MHY3200 ameliorates age-associated renal inflammation by regulating NF-κB and FoxO1 via ROS/Akt signaling.
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Affiliation(s)
- Min Jo Kim
- Department of Pharmacy, College of Pharmacy, Pusan National University, Geumjeong-gu, Busan 46241, Korea; (M.J.K.); (D.H.K.); (E.B.)
| | - Dae Hyun Kim
- Department of Pharmacy, College of Pharmacy, Pusan National University, Geumjeong-gu, Busan 46241, Korea; (M.J.K.); (D.H.K.); (E.B.)
| | - EunJin Bang
- Department of Pharmacy, College of Pharmacy, Pusan National University, Geumjeong-gu, Busan 46241, Korea; (M.J.K.); (D.H.K.); (E.B.)
| | - Sang Gyun Noh
- Interdisciplinary Research Programme of Bioinformatics and Longevity Science, Department of Pharmacy, College of Pharmacy, Pusan National University, Geumjeong-gu, Busan 46241, Korea;
| | - Pusoon Chun
- College of Pharmacy, Inje University, Gimhae 50834, Gyeongsangnam-do, Korea;
| | - Takako Yokozawa
- Graduate School Science and Engineering for Research, University of Toyama, Toyama 930-8555, Japan;
| | - Hyung Ryong Moon
- Department of Pharmacy, College of Pharmacy, Pusan National University, Geumjeong-gu, Busan 46241, Korea; (M.J.K.); (D.H.K.); (E.B.)
| | - Hae Young Chung
- Department of Pharmacy, College of Pharmacy, Pusan National University, Geumjeong-gu, Busan 46241, Korea; (M.J.K.); (D.H.K.); (E.B.)
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Okra ( Abelmoschus Esculentus) as a Potential Dietary Medicine with Nutraceutical Importance for Sustainable Health Applications. Molecules 2021; 26:molecules26030696. [PMID: 33525745 PMCID: PMC7865958 DOI: 10.3390/molecules26030696] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 01/20/2021] [Accepted: 01/22/2021] [Indexed: 02/07/2023] Open
Abstract
Recently, there has been a paradigm shift from conventional therapies to relatively safer phytotherapies. This divergence is crucial for the management of various chronic diseases. Okra (Abelmoschus esculentus L.) is a popular vegetable crop with good nutritional significance, along with certain therapeutic values, which makes it a potential candidate in the use of a variety of nutraceuticals. Different parts of the okra fruit (mucilage, seed, and pods) contain certain important bioactive components, which confer its medicinal properties. The phytochemicals of okra have been studied for their potential therapeutic activities on various chronic diseases, such as type-2 diabetes, cardiovascular, and digestive diseases, as well as the antifatigue effect, liver detoxification, antibacterial, and chemo-preventive activities. Moreover, okra mucilage has been widely used in medicinal applications such as a plasma replacement or blood volume expanders. Overall, okra is considered to be an easily available, low-cost vegetable crop with various nutritional values and potential health benefits. Despite several reports about its therapeutic benefits and potential nutraceutical significance, there is a dearth of research on the pharmacokinetics and bioavailability of okra, which has hampered its widespread use in the nutraceutical industry. This review summarizes the available literature on the bioactive composition of okra and its potential nutraceutical significance. It will also provide a platform for further research on the pharmacokinetics and bioavailability of okra for its possible commercial production as a therapeutic agent against various chronic diseases.
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12
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Kpemissi M, Potârniche AV, Lawson-Evi P, Metowogo K, Melila M, Dramane P, Taulescu M, Chandramohan V, Suhas DS, Puneeth TA, S VK, Vlase L, Andrei S, Eklu-Gadegbeku K, Sevastre B, Veerapur VP. Nephroprotective effect of Combretum micranthum G. Don in nicotinamide-streptozotocin induced diabetic nephropathy in rats: In-vivo and in-silico experiments. JOURNAL OF ETHNOPHARMACOLOGY 2020; 261:113133. [PMID: 32673708 DOI: 10.1016/j.jep.2020.113133] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 06/01/2020] [Accepted: 06/22/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Combretum micranthum G. Don (CM) is extensively used in traditional medicine throughout West Africa and commonly known as "long-life herbal tea" or "plant to heal". Further, traditional healers frequently use the title plant to mitigate of renal disorders. AIM OF THE STUDY To explore the nephroprotective property of standardised hydroalcoholic extract of Combretum micranthum in nicotinamide-streptozotocin induced diabetic nephropathy in rats. In addition, in-silico computational experiments were performed with bioactive compounds of the title plant against PPARα and PPARγ. MATERIAL AND METHODS Male rats were made diabetic by a single intraperitoneal (ip) injection of STZ (50 mg/kg), 15 min after ip administration of NA (100 mg/kg) dissolved in normal saline. The diabetic rats received CM extract (200 and 400 mg/kg p.o.) daily, for eight weeks. Body weights and blood glucose (non-fasting and fasting) of rats were measured weekly. Daily food and water consumption were also measured. After 8 weeks of treatment, urine biochemical parameters such as N-Acetyl-β-D-Glucosaminidase (NAG), urea (UR), uric acid (UA), creatinine (CRE), and serum markers of diabetes, kidney damage and liver damage such as insulin, lipid parameters), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (γGT), albumin (Alb), magnesium (Mg2+), calcium (Ca2+), phosphorus (P), were estimated. Blood glycosylated hemoglobin (HbA1C) were also estimated. kidney and liver were used for biochemical estimation of oxidative stress markers such as lipid peroxidation, superoxide dismutase (SOD) activity and glutathione peroxidase (GPx) activity. The kidney and pancreas were used for histopathological study. Further, HPLC chemoprofiling of CM extract and in-silico molecular simulation experiments were performed. RESULTS At the end of eight weeks, renal damage induced by the consequence of prolong diabetic condition was confirmed by altered levels of serum and urine kidney and liver function markers, oxidative stress markers and histopathological variations in kidney. Treatment with CM extract ameliorated the diabetes mellitus-induced renal biochemical parameters and histopathological changes. Further, HPLC-UV & MS experiments revealed that CM extract contains several bioactive compounds including hyperozide (62.35 μg/mg of extract) and quercitrin (19.07 μg/mg of extract). In-silico experiment exhibited cianidanol (-17.133), epicatechin (-15.107) exhibited higher docking score against PPARα and luteoforol (-11.038), epigallocatechin (-10.736) against PPARγ. Based on docking and drug likeness score, four bioactive compounds were selected for molecular dynamic experiments. Cianidanol and epigallocatechin out of the 30 compounds are concluded as a potential candidate for the treatment of DN through activating PPARα and PPARγ target protein. CONCLUSIONS Taken together, the present study provided the scientific footage for the traditional use of Combretum micranthum.
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Affiliation(s)
- Mabozou Kpemissi
- University of Lomé, Togo; University of Agricultural Science and Veterinary Medicine, Manastur Street. 3-5, 400372, Cluj-Napoca, Romania; Sree Siddaganga College of Pharmacy, B.H. Road, Tumkur, 572 102, Karnataka, India.
| | - Adrian-Valentin Potârniche
- University of Agricultural Science and Veterinary Medicine, Manastur Street. 3-5, 400372, Cluj-Napoca, Romania
| | | | | | | | - Pare Dramane
- University of Ouagadougou UFR/SVT, 09 BP 848, Ouagadougou 09, Burkina Faso
| | - Marian Taulescu
- University of Agricultural Science and Veterinary Medicine, Manastur Street. 3-5, 400372, Cluj-Napoca, Romania
| | - Vivek Chandramohan
- Department of Biotechnology, Siddaganga Institute of Technology, Tumkur, 572103, Karnataka, India
| | | | | | - Vijaya Kumar S
- Sree Siddaganga College of Pharmacy, B.H. Road, Tumkur, 572 102, Karnataka, India
| | - Laurian Vlase
- University of Medicine and Pharmacy "Iuliu Hateganu", Emil Isaac Street 13, 400023, Cluj-Napoca, Romania
| | - Sanda Andrei
- University of Agricultural Science and Veterinary Medicine, Manastur Street. 3-5, 400372, Cluj-Napoca, Romania
| | | | - Bogdan Sevastre
- University of Agricultural Science and Veterinary Medicine, Manastur Street. 3-5, 400372, Cluj-Napoca, Romania
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13
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Luan F, Wu Q, Yang Y, Lv H, Liu D, Gan Z, Zeng N. Traditional Uses, Chemical Constituents, Biological Properties, Clinical Settings, and Toxicities of Abelmoschus manihot L.: A Comprehensive Review. Front Pharmacol 2020; 11:1068. [PMID: 32973492 PMCID: PMC7482509 DOI: 10.3389/fphar.2020.01068] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 06/30/2020] [Indexed: 12/14/2022] Open
Abstract
Abelmoschus manihot, an annual herbal flowering plant, is widely distributed throughout eastern Europe and in temperate and subtropical regions of Asia. Its flowers have been traditionally used for the treatment of chronic kidney disease in China. Currently, more than 128 phytochemical ingredients have been obtained and identified from the flowers, seeds, stems, and leaves of A. manihot. The primary components are flavonoids, amino acids, nucleosides, polysaccharides, organic acids, steroids, and volatile oils. A. manihot and its bioactive constituents possess a plethora of biological properties, including antidiabetic nephropathy, antioxidant, antiadipogenic, anti-inflammatory, analgesic, anticonvulsant, antidepressant, antiviral, antitumor, cardioprotective, antiplatelet, neuroprotective, immunomodulatory, and hepatoprotective activities, and have effects on cerebral infarction, bone loss, etc. However, insufficient utilization and excessive waste have already led to a rapid reduction of resources, meaning that a study on the sustainable use of A. manihot is urgent and necessary. Moreover, the major biologically active constituents and the mechanisms of action of the flowers have yet to be elucidated. The present paper provides an early and comprehensive review of the traditional uses, chemical constituents, pharmacological activities, and pharmaceutical, quality control, toxicological, and clinical settings to emphasize the benefits of this plant and lays a solid foundation for further development of A. manihot.
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Affiliation(s)
- Fei Luan
- Department of Clinical Pharmacy, Shaanxi Provincial Hospital of Tuberculosis Prevention and Treatment, Xi'an, China.,Department of Pharmacology, College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qianhong Wu
- Department of Clinical Pharmacy, Shaanxi Provincial Hospital of Tuberculosis Prevention and Treatment, Xi'an, China
| | - Yan Yang
- Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai, China
| | - Haizhen Lv
- Department of Clinical Pharmacy, Shaanxi Provincial Hospital of Tuberculosis Prevention and Treatment, Xi'an, China
| | - Daoheng Liu
- Department of Clinical Pharmacy, Shaanxi Provincial Hospital of Tuberculosis Prevention and Treatment, Xi'an, China
| | - Zhaoping Gan
- Department of Clinical Pharmacy, Shaanxi Provincial Hospital of Tuberculosis Prevention and Treatment, Xi'an, China
| | - Nan Zeng
- Department of Pharmacology, College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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14
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Yang S, Ma C, Wu H, Zhang H, Yuan F, Yang G, Yang Q, Jia L, Liang Z, Kang L. Tectorigenin attenuates diabetic nephropathy by improving vascular endothelium dysfunction through activating AdipoR1/2 pathway. Pharmacol Res 2020; 153:104678. [PMID: 32014572 DOI: 10.1016/j.phrs.2020.104678] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 01/17/2020] [Accepted: 01/30/2020] [Indexed: 01/10/2023]
Abstract
Diabetic nephropathy (DN), a kind of microvascular complication, is a primary cause of end-stage renal disease worldwide. However, therapeutic drugs for DN treatment are still in lack. The glomerular endothelium is essential to maintain selective permeability of glomerular filtration barrier and glomerular vasculature function. Growing evidences show that endothelial dysfunction or injury is the initial stage of vascular damage in DN, which can be induced by hyperglycemia, lipotoxicity, and inflammation. Therefore, to improve the function of vascular endothelium in kidney is a key point for treatment of DN. As a plant isoflavone, tectorigenin (TEC) has attracted considerable attention due to its anti-proliferative and anti-inflammatory functions. However, whether TEC could inhibit the DN development remains unknown. In this study, we examined the effects of TEC on DN development in db/db mice, a type of genetic defect diabetic mice that can spontaneously develop into severe renal dysfunction. Intriguingly, TEC treatment restored diabetes-induced glucose and lipid metabolic disorder; and improved the deterioration of renal function, particularly the renal endothelium function in db/db mice. Additionally, TEC inhibited the renal inflammation via reducing macrophages infiltration and M1 polarization. Moreover, TEC inhibited lipopolysaccharide (LPS)-induced endothelial injury and M1 polarization in vitro. Mechanistically, TEC partially restored the reduction in expression of adiponectin receptor 1/2 (AdipoR1/2), pi-LKB1, pi-AMPKα, and PPARα in vitro and in vivo. Noteworthy, these beneficial pharmacological activities mediated by TEC were significantly attenuated after AdipoR1/2 knockdown by siRNA, indicating that AdipoR1/2 plays a critical role in protection against DN. Collectively, these results suggested that TEC have a potently effect for retarding type 2 diabetes-associated DN.
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Affiliation(s)
- Shu Yang
- Department of Endocrinology, The 2nd Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China
| | - Chuanrui Ma
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China; Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, Tianjin, China
| | - Han Wu
- Department of Endocrinology, The 2nd Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China; Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Hao Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China; Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, Tianjin, China
| | - Fengyi Yuan
- Department of Endocrinology, The 2nd Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China
| | - Guangyan Yang
- Department of Endocrinology, The 2nd Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China
| | - Qi Yang
- Department of Endocrinology, The 2nd Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China
| | - Lijing Jia
- Department of Endocrinology, The 2nd Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China.
| | - Zhen Liang
- Department of Endocrinology, The 2nd Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China.
| | - Lin Kang
- Department of Endocrinology, The 2nd Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China.
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15
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Abstract
Increasing evidence suggests that renal inflammation contributes to the pathogenesis and progression of diabetic kidney disease (DKD) and that anti-inflammatory therapies might have renoprotective effects in DKD. Immune cells and resident renal cells that activate innate immunity have critical roles in triggering and sustaining inflammation in this setting. Evidence from clinical and experimental studies suggests that several innate immune pathways have potential roles in the pathogenesis and progression of DKD. Toll-like receptors detect endogenous danger-associated molecular patterns generated during diabetes and induce a sterile tubulointerstitial inflammatory response via the NF-κB signalling pathway. The NLRP3 inflammasome links sensing of metabolic stress in the diabetic kidney to activation of pro-inflammatory cascades via the induction of IL-1β and IL-18. The kallikrein-kinin system promotes inflammatory processes via the generation of bradykinins and the activation of bradykinin receptors, and activation of protease-activated receptors on kidney cells by coagulation enzymes contributes to renal inflammation and fibrosis in DKD. In addition, hyperglycaemia leads to protein glycation and activation of the complement cascade via recognition of glycated proteins by mannan-binding lectin and/or dysfunction of glycated complement regulatory proteins. Data from preclinical studies suggest that targeting these innate immune pathways could lead to novel therapies for DKD.
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16
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Wu Y, Chen F, Huang X, Zhang R, Yu Z, Chen Z, Liu J. Berberine (BBR) Attenuated Palmitic Acid (PA)-Induced Lipotoxicity in Human HK-2 Cells by Promoting Peroxisome Proliferator-Activated Receptor α (PPAR-α). Med Sci Monit 2019; 25:7702-7708. [PMID: 31607744 PMCID: PMC6812469 DOI: 10.12659/msm.916686] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 05/21/2019] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Berberine (BBR), a natural alkaloid isolated from Coptis chinensis, has frequently been reported as an antidiabetic reagent, partly due to its lipid-lowering activity. Evidence suggests that BBR ameliorates palmitate-induced lipid deposition and apoptosis in renal tubular epithelial cells (TECs), which tracks in tandem with the enhancement of peroxisome proliferator-activated receptor alpha (PPAR-alpha). The study aim was to investigate the roles of BBR in renal lipotoxicity in vitro, and investigate whether PPAR-alpha was the underlying mechanism. MATERIAL AND METHODS Human TECs (HK-2 cells) were injured with palmitic acid (PA), and then treated with BBR, BBR+PPAR-alpha inhibitor (GW6471), and PA+PPAR-alpha agonist (fenofibrate). Endoplasmic reticulum (ER) stress was assessed by measuring the expression of prospective evaluation of radial keratotomy (PERK), C/EBP-homologous protein (CHOP), and 78 kDa glucose-regulated protein (GRP78). Lipid metabolism was assessed by determining lipid anabolism-associated genes, including fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and lipoprotein lipase (LPL), as well as lipid catabolism-associated gene, including carnitine palmitoyl transferase 1 (CPT1). Inflammatory response of HK-2 cells was evaluated by measuring interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha. Cell apoptosis and protein levels of cleaved-caspase-3 were evaluated. RESULTS PA downregulated PPAR-alpha and induced server lipotoxicity in HK-2 cells by ER stress, increasing lipid deposition, and elevating inflammatory response of HK-2 cells accompanied with inducting cell apoptosis and cleaved-caspase-3, which were obviously reversed by additional treatment of BBR or PPAR-alpha agonist. However, the protective effect of BBR in PA-induced lipotoxicity in HK-2 cells was significantly ameliorated by PPAR-alpha inhibitor. CONCLUSIONS BBR attenuated PA-induced lipotoxicity via the PPAR-alpha pathway.
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17
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Kim EN, Lim JH, Kim MY, Ban TH, Jang IA, Yoon HE, Park CW, Chang YS, Choi BS. Resveratrol, an Nrf2 activator, ameliorates aging-related progressive renal injury. Aging (Albany NY) 2019; 10:83-99. [PMID: 29326403 PMCID: PMC5811244 DOI: 10.18632/aging.101361] [Citation(s) in RCA: 150] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Accepted: 01/07/2018] [Indexed: 01/08/2023]
Abstract
Background. Two important issues in the aging kidney are mitochondrial dysfunction and oxidative stress. An Nrf2 activator, resveratrol, is known to have various effects. Resveratrol may prevent inflammation and oxidative stress by activating Nrf2 and SIRT1 signaling. We examined whether resveratrol could potentially ameliorate the cellular condition, such as renal injury due to cellular oxidative stress and mitochondrial dysfunction caused by aging. Methods. Male 18-month-old C57BL/6 mice were used. Resveratrol (40 mg/kg) was administered to aged mice for 6 months. We compared histological changes, oxidative stress, and aging-related protein expression in the kidney between the resveratrol-treated group (RSV) and the control group (cont). We performed experiments using small-interfering RNAs (siRNAs) for Nrf2 and SIRT1 in cultured HK2 cells. Results. Resveratrol improved renal function, proteinuria, histological changes and inflammation in aging mice. Also, expression of Nrf2-HO-1-NOQ-1 signaling and SIRT1-AMPK-PGC-1α signaling was increased in the RSV group. Transfection with Nrf2 and SIRT1 siRNA prevented resveratrol-induced anti-oxidative effect in HK2 cells in media treated with H2O2. Conclusions. Activation of the Nrf2 and SIRT1 signaling pathways ameliorated oxidative stress and mitochondrial dysfunction. Pharmacological targeting of Nrf2 signaling molecules may reduce the pathologic changes of aging in the kidney.
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Affiliation(s)
- Eun Nim Kim
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ji Hee Lim
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Min Young Kim
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Tae Hyun Ban
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - In-Ae Jang
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hye Eun Yoon
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Cheol Whee Park
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yoon Sik Chang
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Bum Soon Choi
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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18
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Molecular targets of fenofibrate in the cardiovascular-renal axis: A unifying perspective of its pleiotropic benefits. Pharmacol Res 2019; 144:132-141. [PMID: 30970278 DOI: 10.1016/j.phrs.2019.03.025] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 03/28/2019] [Accepted: 03/29/2019] [Indexed: 12/17/2022]
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19
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Allinovi M, De Chiara L, Angelotti ML, Becherucci F, Romagnani P. Anti-fibrotic treatments: A review of clinical evidence. Matrix Biol 2018; 68-69:333-354. [DOI: 10.1016/j.matbio.2018.02.017] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 02/19/2018] [Accepted: 02/20/2018] [Indexed: 02/06/2023]
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20
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Kim EN, Kim MY, Lim JH, Kim Y, Shin SJ, Park CW, Kim YS, Chang YS, Yoon HE, Choi BS. The protective effect of resveratrol on vascular aging by modulation of the renin-angiotensin system. Atherosclerosis 2018; 270:123-131. [PMID: 29407880 DOI: 10.1016/j.atherosclerosis.2018.01.043] [Citation(s) in RCA: 104] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 12/18/2017] [Accepted: 01/24/2018] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIMS This study evaluated the effects of resveratrol on arterial aging and the renin-angiotensin system (RAS) in mice and vascular smooth muscle cells (VSMCs). METHODS Aging mice were divided into control and resveratrol groups. Histological changes, inflammation, oxidative stress, RAS components, and the expression of AMP-activated protein kinase (AMPK), silent information regulator T1 (SIRT1), peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α), and anti-oxidative enzymes was measured in thoracic aortas of 24-month-old mice. The effect of resveratrol on fibrosis, cell senescence, and RAS components was also investigated in VSMCs stimulated by angiotensin (Ang) II. RESULTS Aorta media thickness, inflammation, fibrosis, and oxidative stress were significantly lower in the resveratrol group than in the control group. Resveratrol treatment decreased serum Ang II level and the aortic expression of prorenin receptor (PRR) and angiotensin converting enzyme (ACE), and increased serum Ang-(1-7) level and the expression of ACE2, Ang II type 2 receptor (AT2R), and Mas receptor (MasR). Resveratrol increased the expression of phosphorylated AMPK, SIRT1, PGC-1α, phosphorylated endothelial nitric oxide synthase and superoxide dismutase 1 and 2, and decreased that of NADPH oxidase 2 and 4. In Ang II-stimulated VSMCs, resveratrol treatment markedly decreased the number of senescence associated β-galactosidase stained cells and pro-fibrotic protein expression and increased the expression of AT2R and MasR. CONCLUSIONS Resveratrol protects against arterial aging and this effect is associated with reduced activity of the PRR-ACE-Ang II axis and stimulation of the ACE2-Ang-(1-7)-ATR2-MasR axis.
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MESH Headings
- AMP-Activated Protein Kinases/metabolism
- Age Factors
- Aging
- Animals
- Anti-Inflammatory Agents/pharmacology
- Antioxidants/pharmacology
- Aorta, Thoracic/drug effects
- Aorta, Thoracic/metabolism
- Aorta, Thoracic/pathology
- Cells, Cultured
- Cellular Senescence/drug effects
- Fibrosis
- Gene Expression Regulation
- Male
- Mice, Inbred C57BL
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Oxidative Stress/drug effects
- PPAR alpha/metabolism
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
- Renin-Angiotensin System/drug effects
- Renin-Angiotensin System/genetics
- Resveratrol/pharmacology
- Signal Transduction/drug effects
- Sirtuin 1/metabolism
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Affiliation(s)
- Eun Nim Kim
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Republic of Korea
| | - Min Young Kim
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Republic of Korea
| | - Ji Hee Lim
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Republic of Korea
| | - Yaeni Kim
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Republic of Korea; Department of Internal Medicine, Incheon St. Mary's Hospital, Incheon, Republic of Korea
| | - Seok Joon Shin
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Republic of Korea; Department of Internal Medicine, Incheon St. Mary's Hospital, Incheon, Republic of Korea
| | - Cheol Whee Park
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Republic of Korea; Department of Internal Medicine, Seoul St. Mary's Hospital, Seoul, Republic of Korea
| | - Yong-Soo Kim
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Republic of Korea; Department of Internal Medicine, Seoul St. Mary's Hospital, Seoul, Republic of Korea
| | - Yoon Sik Chang
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Republic of Korea; Department of Internal Medicine, Yeouido St. Mary's Hospital, Seoul, Republic of Korea
| | - Hye Eun Yoon
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Republic of Korea; Department of Internal Medicine, Incheon St. Mary's Hospital, Incheon, Republic of Korea.
| | - Bum Soon Choi
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Republic of Korea; Department of Internal Medicine, Seoul St. Mary's Hospital, Seoul, Republic of Korea.
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Liu S, Ye L, Tao J, Ge C, Huang L, Yu J. Total flavones of Abelmoschus manihot improve diabetic nephropathy by inhibiting the iRhom2/TACE signalling pathway activity in rats. PHARMACEUTICAL BIOLOGY 2017; 56:1-11. [PMID: 29221422 PMCID: PMC6130561 DOI: 10.1080/13880209.2017.1412467] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 10/14/2017] [Accepted: 11/29/2017] [Indexed: 05/21/2023]
Abstract
CONTEXT Total flavones extracted from Abelmoschus manihot L. (Malvaceae) medic (TFA) have been proven clinically effective at improving renal inflammation and glomerular injury in chronic kidney disease (CKD). OBJECTIVE This study evaluated the function of TFA as an inhibitor of iRhom2/TACE (tumour necrosis factor-α converting enzyme) signalling and investigated its anti-DN (diabetic nephropathy) effects in a DN rat model. MATERIALS AND METHODS In vitro, cells were treated with 200 μg/mL advanced glycation end products (AGEs), and then co-cultured with 20 μg/mL TFA for 24 h. Real time PCR, western blotting and co-immunoprecipitation assays were performed. In vivo, DN was induced in 8 week old male Sprague-Dawley rats via unilateral nephrectomy and intraperitoneal injection of streptozotocin, then TFA were administered to rats by gavage for 12 weeks at three different doses (300, 135 and 75 mg/kg/d). 4-Phenylbutanoic acid (2.5 mg/kg/d) was used as a positive control. RESULTS IC50 of TFA is 35.6 μM in HK2 and 39.6 μM in HRMC. TFA treatment (20 μM) inhibited the activation of iRhom2/TACE signalling in cultured cells induced by AGEs. LD50>26 g/kg and ED50=67 mg/kg of TFA in rat by gavage, TFA dose-dependently downregulated the expression of proinflammatory cytokines and exerted anti-inflammatory effects significantly though inhibiting the activation of iRhom2/TACE signalling. DISCUSSION AND CONCLUSIONS Our results show that TFA could dose-dependently ameliorate renal inflammation by inhibiting the activation of iRhom2/TACE signalling and attenuating ER stress. These results suggest that TFA has potential therapeutic value for the treatment of DN in humans.
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Affiliation(s)
- Su Liu
- Department of Endocrinology, Jiangsu Province Hosipital of TCM, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Lifang Ye
- Department of Endocrinology, Jiangsu Province Hosipital of TCM, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jing Tao
- Department of Nephrology, Jiangsu Province Hosipital of TCM, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Chao Ge
- Department of Gastroenterology, Jiangsu Province Hosipital of TCM, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Liji Huang
- Department of Endocrinology, Jiangsu Province Hosipital of TCM, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jiangyi Yu
- Department of Endocrinology, Jiangsu Province Hosipital of TCM, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- CONTACT Jiangyi YuDepartment of Endocrinology, Jiangsu Province Hosipital of TCM, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
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PPARα activation by MHY908 attenuates age-related renal inflammation through modulation of the ROS/Akt/FoxO1 pathway. Exp Gerontol 2017; 92:87-95. [PMID: 28323024 DOI: 10.1016/j.exger.2017.03.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 02/28/2017] [Accepted: 03/14/2017] [Indexed: 01/21/2023]
Abstract
2-[4-(5-Chlorobenzothiazothiazol-2-yl)phenoxy]-2-methyl-propionic acid (MHY908) has been shown to prevent insulin resistance-induced hyperinsulinemia in aged rats. However, the mechanism underlying MHY908-mediated amelioration of renal inflammation with insulin resistance during aging remains unknown. This study investigated the effects of MHY908 on age-related changes in the IRS/Akt/forkhead box (FoxO) 1 signaling pathway in the kidneys of aged rats and HEK293T cells. Experiments were performed in young, old, and MHY908-fed old rats (1mg or 3mg/kg/day MHY908 for 4 weeks). We found that MHY908-fed old rats suppressed phosphorylation of IRS/Akt and induced FoxO1 activation, leading to increased expression of MnSOD and catalase. In addition, in insulin-treated cells, MHY908 prevented the FoxO1 inactivation and increased the expression of MnSOD and catalase by inactivating IRS and Akt. In contrast, NF-κB signaling pathway decreased with MHY908 treatment in insulin-treated cells. Furthermore, MHY908 exclusively activated peroxisome proliferator-activated receptor (PPAR) α in the kidneys, leading to the inhibition of insulin-induced NADPH oxidase subunit 4 (NOX4)-derived reactive oxygen species (ROS) generation and FoxO1 inactivation. In conclusion, MHY908 improved the hyperinsulinemia-induced pro-inflammatory response through NF-κB inactivation and FoxO1 activation in aged rat kidneys. These phenomena suggest that PPARα activation by MHY908 attenuates NOX4-derived ROS generation in response to insulin.
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Cheng R, Ding L, He X, Takahashi Y, Ma JX. Interaction of PPARα With the Canonic Wnt Pathway in the Regulation of Renal Fibrosis. Diabetes 2016; 65:3730-3743. [PMID: 27543085 PMCID: PMC5127249 DOI: 10.2337/db16-0426] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 09/04/2016] [Indexed: 01/02/2023]
Abstract
Peroxisome proliferator-activated receptor-α (PPARα) displays renoprotective effects with an unclear mechanism. Aberrant activation of the canonical Wnt pathway plays a key role in renal fibrosis. Renal levels of PPARα were downregulated in both type 1 and type 2 diabetes models. The PPARα agonist fenofibrate and overexpression of PPARα both attenuated the expression of fibrotic factors, and suppressed high glucose-induced or Wnt3a-induced Wnt signaling in renal cells. Fenofibrate inhibited Wnt signaling in the kidney of diabetic rats. A more renal prominent activation of Wnt signaling was detected both in PPARα-/- mice with diabetes or obstructive nephropathy and in PPARα-/- tubular cells treated with Wnt3a. PPARα did not block the transcriptional activity of β-catenin induced by a constitutively active mutant of lipoprotein receptor-related protein 6 (LRP6) or β-catenin. LRP6 stability was decreased by overexpression of PPARα and increased in PPARα-/- tubular cells, suggesting that PPARα interacts with Wnt signaling at the Wnt coreceptor level. 4-Hydroxynonenal-induced reactive oxygen species production, which resulted in LRP6 stability, was suppressed by overexpression of PPARα and dramatically enhanced in PPARα-/- tubular cells. Diabetic PPARα-/- mice showed more prominent NADPH oxidase-4 overexpression compared with diabetic wild-type mice, suggesting that the inhibitory effect of PPARα on Wnt signaling may be ascribed to its antioxidant activity. These observations identified a novel interaction between PPARα and the Wnt pathway, which is responsible, at least partially, for the therapeutic effects of fenofibrate on diabetic nephropathy.
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Affiliation(s)
- Rui Cheng
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Lexi Ding
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Xuemin He
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Yusuke Takahashi
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Jian-Xing Ma
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
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Ge J, Miao JJ, Sun XY, Yu JY. Huangkui capsule, an extract from Abelmoschus manihot (L.) medic, improves diabetic nephropathy via activating peroxisome proliferator-activated receptor (PPAR)-α/γ and attenuating endoplasmic reticulum stress in rats. JOURNAL OF ETHNOPHARMACOLOGY 2016; 189:238-49. [PMID: 27224243 DOI: 10.1016/j.jep.2016.05.033] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Revised: 04/29/2016] [Accepted: 05/14/2016] [Indexed: 05/21/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Abelmoschus manihot (L.) medic (AM) is a natural medicinal plant used for the treatment of chronic kidney disease (CKD) in China. Huangkui capsule (HKC), an extract from AM, has been proved clinically effective in improving renal inflammation and glomerular injury in CKD. However, the mechanisms of HKC are still not fully understood. AIM OF THE STUDY Peroxisome proliferator-activated receptor (PPAR)-α/γ dual agonists have the potential to be used as therapeutic agents for the treatment of type 2 diabetes and diabetic nephropathy (DN). This study evaluated the function of Huangkui capsule (HKC), an extract from Abelmoschus manihot (L.) medic (AM), as a dual agonist for PPARα/γ and investigated its anti-DN effects in a DN rat model. MATERIALS AND METHODS ChIP and reporter gene assays were performed and the expression of PPARα/γ target genes was monitored to examine the ability of HKC to activate PPARα/γ. DN was induced in male Sprague-Dawley rats via unilateral nephrectomy and intraperitoneal injection of streptozotocin. HKC was administered to the diabetic nephropathy rats at three different doses: high dose HKC (300mg/kg/d); middle dose HKC (175mg/kg/d); and low dose HKC (75mg/kg/d). Irbesartan (4mg/kg/d body weight) was used as a positive control. Following 12 weeks' treatment, we measured general status, renal morphological appearance, proteinuria, blood biochemical parameters, and glomerular morphological changes. The expression of collagen IV, TGFβ, TNFα and IL-6 in renal tissue was evaluated. Endoplasmic reticulum (ER) stress in renal tissue was also analyzed. RESULTS HKC enhanced the transcriptional activity of PPARα and PPARγ in cultured cells, livers and kidneys of DN rats, and it reduced serum triglyceride and cholesterol levels and fat in livers of DN rats. Furthermore, HKC reduced the expressions of inflammatory genes in kidneys of DN rats. Strikingly, HKC reduced ER stress and c-Jun NH2-terminal kinase activation in the liver and kidney of DN rats and subsequently improved renal injury. CONCLUSIONS Our results show that HKC improved lipid metabolic disorders by activating PPARα/γ and attenuating ER stress. HKC could dose-dependently ameliorate renal inflammation and glomerular injury in DN rats. These results suggest that HKC has potential as an anti-DN agent for the treatment of DN in humans.
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Affiliation(s)
- Jing Ge
- Jiangsu Province Hosipital of TCM, Affiliated Hospital of Nanjing University of TCM, Nanjing Hanzhong Road, Nanjing, China
| | - Jun-Jun Miao
- Jiangsu Province Hosipital of TCM, Affiliated Hospital of Nanjing University of TCM, Nanjing Hanzhong Road, Nanjing, China
| | - Xin-Yi Sun
- Jiangsu Province Hosipital of TCM, Affiliated Hospital of Nanjing University of TCM, Nanjing Hanzhong Road, Nanjing, China
| | - Jiang-Yi Yu
- Jiangsu Province Hosipital of TCM, Affiliated Hospital of Nanjing University of TCM, Nanjing Hanzhong Road, Nanjing, China.
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Sohn M, Kim K, Uddin MJ, Lee G, Hwang I, Kang H, Kim H, Lee JH, Ha H. Delayed treatment with fenofibrate protects against high-fat diet-induced kidney injury in mice: the possible role of AMPK autophagy. Am J Physiol Renal Physiol 2016; 312:F323-F334. [PMID: 27465995 DOI: 10.1152/ajprenal.00596.2015] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 07/22/2016] [Indexed: 11/22/2022] Open
Abstract
Fenofibrate activates not only peroxisome proliferator-activated receptor-α (PPARα) but also adenosine monophosphate-activated protein kinase (AMPK). AMPK-mediated cellular responses protect kidney from high-fat diet (HFD)-induced injury, and autophagy resulting from AMPK activation has been regarded as a stress-response mechanism. Thus the present study examined the role of AMPK and autophagy in the renotherapeutic effects of fenofibrate. C57BL/6J mice were divided into three groups: normal diet (ND), HFD, and HFD + fenofibrate (HFD + FF). Fenofibrate was administered 4 wk after the initiation of the HFD when renal injury was initiated. Mouse proximal tubule cells (mProx24) were used to clarify the role of AMPK. Feeding mice with HFD for 12 wk induced insulin resistance and kidney injury such as albuminuria, glomerulosclerosis, tubular injury, and inflammation, which were effectively inhibited by fenofibrate. In addition, fenofibrate treatment resulted in the activation of renal AMPK, upregulation of fatty acid oxidation (FAO) enzymes and antioxidants, and induction of autophagy in the HFD mice. In mProx24 cells, fenofibrate activated AMPK in a concentration-dependent manner, upregulated FAO enzymes and antioxidants, and induced autophagy, all of which were inhibited by treatment of compound C, an AMPK inhibitor. Fenofibrate-induced autophagy was also significantly blocked by AMPKα1 siRNA but not by PPARα siRNA. Collectively, these results demonstrate that delayed treatment with fenofibrate has a therapeutic effect on HFD-induced kidney injury, at least in part, through the activation of AMPK and induction of subsequent downstream effectors: autophagy, FAO enzymes, and antioxidants.
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Affiliation(s)
- Minji Sohn
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea
| | - Keumji Kim
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea
| | - Md Jamal Uddin
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea
| | - Gayoung Lee
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea
| | - Inah Hwang
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea
| | - Hyeji Kang
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea
| | - Hyunji Kim
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea
| | - Jung Hwa Lee
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea
| | - Hunjoo Ha
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea
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Varatharajan R, Lim LX, Tan K, Tay CS, Teoh YL, Akhtar SS, Rupeshkumar M, Chung I, Abdullah NA, Banik U, Dhanaraj SA, Balakumar P. Effect of edaravone in diabetes mellitus-induced nephropathy in rats. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2016; 20:333-40. [PMID: 27382349 PMCID: PMC4930901 DOI: 10.4196/kjpp.2016.20.4.333] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Revised: 01/26/2015] [Accepted: 07/14/2015] [Indexed: 11/15/2022]
Abstract
Edaravone, a synthetic-free radical scavenger, has been reported to reduce ischemia-reperfusion-induced renal injury by improving tubular cell function, and lowering serum creatinine and renal vascular resistance. The present study investigated the effect of edaravone in diabetes mellitus-induced nephropathy in rats. A single administration of streptozotocin (STZ, 55 mg/kg, i.p.) was employed to induce diabetes mellitus in rats. The STZ-administered diabetic rats were allowed for 10 weeks to develop nephropathy. Mean body weight, lipid alteration, renal functional and histopathology were analysed. Diabetic rats developed nephropathy as evidenced by a significant increase in serum creatinine and urea, and marked renal histopathological abnormalities like glomerulosclerosis and tubular cell degeneration. The kidney weight to body weight ratio was increased. Moreover, diabetic rats showed lipid alteration as evidenced by a signifi cant increase in serum triglycerides and decrease in serum high-density lipoproteins. Edaravone (10 mg/kg, i.p., last 4-weeks) treatment markedly prevented the development of nephropathy in diabetic rats by reducing serum creatinine and urea and preventing renal structural abnormalities. In addition, its treatment, without significantly altering the elevated glucose level in diabetic rats, prevented diabetes mellitus-induced lipid alteration by reducing serum triglycerides and increasing serum high-density lipoproteins. Interestingly, the renoprotective effect of edaravone was comparable to that of lisinopril (5 mg/kg, p.o, 4 weeks, standard drug). Edaravone prevented renal structural and functional abnormalities and lipid alteration associated with experimental diabetes mellitus. Edaravone has a potential to prevent nephropathy without showing an anti-diabetic action, implicating its direct renoprotection in diabetic rats.
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Affiliation(s)
- Rajavel Varatharajan
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah Darul Aman, Malaysia.; Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Li Xin Lim
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah Darul Aman, Malaysia
| | - Kelly Tan
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah Darul Aman, Malaysia
| | - Chai Sze Tay
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah Darul Aman, Malaysia
| | - Yi Leng Teoh
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah Darul Aman, Malaysia
| | - Shaikh Sohrab Akhtar
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah Darul Aman, Malaysia
| | - Mani Rupeshkumar
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah Darul Aman, Malaysia
| | - Ivy Chung
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Nor Azizan Abdullah
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Urmila Banik
- Pathology Unit, Faculty of Medicine, AIMST University, Semeling, 08100 Bedong, Kedah Darul Aman, Malaysia
| | - Sokkalingam A Dhanaraj
- Pharmaceutical Technology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah Darul Aman, Malaysia
| | - Pitchai Balakumar
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah Darul Aman, Malaysia
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Garg M, Khanna D, Kalra S, Balakumar P. Chronic oral administration of low-dose combination of fenofibrate and rosuvastatin protects the rat heart against experimentally induced acute myocardial infarction. Fundam Clin Pharmacol 2016; 30:394-405. [DOI: 10.1111/fcp.12204] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2015] [Revised: 03/26/2016] [Accepted: 04/26/2016] [Indexed: 12/25/2022]
Affiliation(s)
- Monika Garg
- Cardiovascular Pharmacology Division; Department of Pharmacology; Rajendra Institute of Technology and Sciences; Sirsa 125 055 Haryana India
| | - Deepa Khanna
- Cardiovascular Pharmacology Division; Department of Pharmacology; Rajendra Institute of Technology and Sciences; Sirsa 125 055 Haryana India
| | - Sanjeev Kalra
- Cardiovascular Pharmacology Division; Department of Pharmacology; Rajendra Institute of Technology and Sciences; Sirsa 125 055 Haryana India
| | - Pitchai Balakumar
- Pharmacology Unit; Faculty of Pharmacy; AIMST University; Semeling 08100 Bedong Kedah DarulAman Malaysia
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Wang M, Wang S, Yao D, Yan Q, Lu W. A novel long non-coding RNA CYP4B1-PS1-001 regulates proliferation and fibrosis in diabetic nephropathy. Mol Cell Endocrinol 2016; 426:136-45. [PMID: 26923441 DOI: 10.1016/j.mce.2016.02.020] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2015] [Revised: 02/22/2016] [Accepted: 02/23/2016] [Indexed: 01/10/2023]
Abstract
Diabetic nephropathy is an important microvascular complication of diabetes, and the incidence of end-stage renal disease caused by it are rising annually. Long non-coding RNAs (lncRNAs) are widely regarded to associate with the occurrence and development of various diseases; however, the relationship between lncRNAs and diabetic nephropathy remains largely unknown. This work studied the effect of lncRNAs on diabetic nephropathy pathogenesis. LncRNA microarrays were initially used to detect lncRNAs with altered expression in three cases of kidney tissue from db/db mice with diabetic nephropathy. LncRNAs with differential expression (>2-fold) could be considered candidates. Particularly, CYP4B1-PS1-001 was significantly downregulated in response to early diabetic nephropathy in vitro and in vivo, while overexpression of CYP4B1-PS1-001 inhibited proliferation and fibrosis of mesangial cells. Overall, our data indicate the potential role of CYP4B1-PS1-001 in the proliferation and fibrosis of mice mesangial cells as the prominent features during early stage of diabetic nephropathy, which extend the relationship between lncRNAs and diabetic nephropathy, and may provide a potential therapeutic target and molecular biomarker for the disease.
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Affiliation(s)
- Min Wang
- Department of Endocrinology and Metabolism, Huai'an First People's Hospital, Nanjing Medical University, 6 Beijing Road West, Huai'an, Jiangsu 223300, PR China
| | - Suyu Wang
- Department of Endocrinology and Metabolism, Huai'an First People's Hospital, Nanjing Medical University, 6 Beijing Road West, Huai'an, Jiangsu 223300, PR China
| | - Di Yao
- Department of Endocrinology and Metabolism, Huai'an First People's Hospital, Nanjing Medical University, 6 Beijing Road West, Huai'an, Jiangsu 223300, PR China
| | - Qin Yan
- Department of Microbiology, Nanjing Medical University, Nanjing 210029, PR China.
| | - Weiping Lu
- Department of Endocrinology and Metabolism, Huai'an First People's Hospital, Nanjing Medical University, 6 Beijing Road West, Huai'an, Jiangsu 223300, PR China.
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Kim EN, Lim JH, Kim MY, Kim HW, Park CW, Chang YS, Choi BS. PPARα agonist, fenofibrate, ameliorates age-related renal injury. Exp Gerontol 2016; 81:42-50. [PMID: 27130813 DOI: 10.1016/j.exger.2016.04.021] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Revised: 02/01/2016] [Accepted: 04/25/2016] [Indexed: 11/29/2022]
Abstract
The kidney ages quickly compared with other organs. Expression of senescence markers reflects changes in the energy metabolism in the kidney. Two important issues in aging are mitochondrial dysfunction and oxidative stress. Peroxisome proliferator-activated receptor α (PPARα) is a member of the ligand-activated nuclear receptor superfamily. PPARα plays a major role as a transcription factor that regulates the expression of genes involved in various processes. In this study, 18-month-old male C57BL/6 mice were divided into two groups, the control group (n=7) and the fenofibrate-treated group (n=7) was fed the normal chow plus fenofibrate for 6months. The PPARα agonist, fenofibrate, improved renal function, proteinuria, histological change (glomerulosclerosis and tubular interstitial fibrosis), inflammation, and apoptosis in aging mice. This protective effect against age-related renal injury occurred through the activation of AMPK and SIRT1 signaling. The activation of AMPK and SIRT1 allowed for the concurrent deacetylation and phosphorylation of their target molecules and decreased the kidney's susceptibility to age-related changes. Activation of the AMPK-FOXO3a and AMPK-PGC-1α signaling pathways ameliorated oxidative stress and mitochondrial dysfunction. Our results suggest that activation of PPARα and AMPK-SIRT1 signaling may have protective effects against age-related renal injury. Pharmacological targeting of PPARα and AMPK-SIRT1 signaling molecules may prevent or attenuate age-related pathological changes in the kidney.
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Affiliation(s)
- Eun Nim Kim
- Division of Nephrology, Department of Internal, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ji Hee Lim
- Division of Nephrology, Department of Internal, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Min Young Kim
- Division of Nephrology, Department of Internal, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hyung Wook Kim
- Division of Nephrology, Department of Internal, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Cheol Whee Park
- Division of Nephrology, Department of Internal, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yoon Sik Chang
- Division of Nephrology, Department of Internal, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Bum Soon Choi
- Division of Nephrology, Department of Internal, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
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Du C, Shi Y, Ren Y, Wu H, Yao F, Wei J, Wu M, Hou Y, Duan H. Anthocyanins inhibit high-glucose-induced cholesterol accumulation and inflammation by activating LXRα pathway in HK-2 cells. DRUG DESIGN DEVELOPMENT AND THERAPY 2015; 9:5099-113. [PMID: 26379423 PMCID: PMC4567235 DOI: 10.2147/dddt.s90201] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The dysregulation of cholesterol metabolism and inflammation plays a significant role in the progression of diabetic nephropathy (DN). Anthocyanins are polyphenols widely distributed in food and exert various biological effects including antioxidative, anti-inflammatory, and antihyperlipidemic effects. However, it remains unclear whether anthocyanins are associated with DN, and the mechanisms involved in the reciprocal regulation of inflammation and cholesterol efflux are yet to be elucidated. In this study, we evaluated the regulation of cholesterol metabolism and the anti-inflammatory effects exerted by anthocyanins (cyanidin-3-O-β-glucoside chloride [C3G] or cyanidin chloride [Cy]) and investigated the underlying molecular mechanism of action using high-glucose (HG)-stimulated HK-2 cells. We found that anthocyanins enhanced cholesterol efflux and ABCA1 expression markedly in HK-2 cells. In addition, they increased peroxisome proliferator-activated receptor alpha (PPARα) and liver X receptor alpha (LXRα) expression and decreased the HG-induced expression of the proinflammatory cytokines intercellular adhesion molecule-1 (ICAM1), monocyte chemoattractant protein-1 (MCP1), and transforming growth factor-β1 (TGFβ1), as well as NFκB activation. Incubation with the PPARα-specific inhibitor GW6471 and LXRα shRNA attenuated the anthocyanin-mediated promotion of ABCA1 expression and cholesterol efflux, suggesting that anthocyanins activated PPARα-LXRα-ABCA1-dependent cholesterol efflux in HK-2 cells. Moreover, the knockout of LXRα abrogated the anti-inflammatory effect of anthocyanins, whereas the PPARα antagonist GW6471 does not have this effect. Further investigations revealed that LXRα might interfere with anthocyanin-induced decreased ICAM1, MCP1, and TGFβ1 expression by reducing the nuclear translocation of NFκB. Collectively, these findings suggest that blocking cholesterol deposition and inhibiting the LXRα pathway-induced inflammatory response might be one of the main mechanisms by which anthocyanins exert their protective effects in DN.
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Affiliation(s)
- Chunyang Du
- Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China
| | - Yonghong Shi
- Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China
| | - Yunzhuo Ren
- Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China
| | - Haijiang Wu
- Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China
| | - Fang Yao
- Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China
| | - Jinying Wei
- Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China
| | - Ming Wu
- Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China
| | - Yanjuan Hou
- Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China
| | - Huijun Duan
- Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China
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Pappa M, Dounousi E, Duni A, Katopodis K. Less known pathophysiological mechanisms of anemia in patients with diabetic nephropathy. Int Urol Nephrol 2015; 47:1365-72. [PMID: 26017902 DOI: 10.1007/s11255-015-1012-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 05/12/2015] [Indexed: 12/11/2022]
Abstract
Diabetes mellitus (DM) is currently considered a modern global epidemic, and diabetic nephropathy (DN) is the most common cause of chronic kidney disease (CKD). Anemia is one of the most significant complications of CKD, and it is mainly attributed to insufficient erythropoietin (EPO) production. However, anemia develops earlier in the course of CKD among patients with DM, and the severity of anemia tends to be more marked in these patients compared to nondiabetic subjects, regardless of the stage of CKD. In this review, we focus on the "less known" complex interacting mechanisms which are involved in the pathophysiology of anemia associated with DN. Although the major cause of anemia in DN is considered to be an inappropriate response of the plasma EPO concentration to anemia, several other possible mechanisms have been suggested. Glomerular hyperfiltration, proteinuria, renal tubular dysfunction and interstitial fibrosis are among the main culprits. On the other hand, systemic effects such as chronic inflammation, autonomic neuropathy and the renin-angiotensin system are also involved. Finally, several medications are considered to aggravate anemia associated with DN. Since anemia is an important predictor of quality of life and is implicated in the increased burden of cardiovascular morbidity and mortality, further research is required to elucidate its pathogenesis in diabetic patients.
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Affiliation(s)
- M Pappa
- Department of Nephrology, General Hospital of Arta, Arta, Greece
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Al-Rasheed NM, Al-Rasheed NM, Attia HA, Al-Amin MA, Al-Ajmi HN, Hasan IH, Mohamad RA, Sinjilawi NA. Renoprotective Effects of Fenofibrate via Modulation of LKB1/AMPK mRNA Expression and Endothelial Dysfunction in a Rat Model of Diabetic Nephropathy. Pharmacology 2015; 95:229-39. [PMID: 25967095 DOI: 10.1159/000381190] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 02/21/2015] [Indexed: 11/19/2022]
Abstract
This study was conducted to investigate whether the renoprotective effects of fenofibrate are mediated via attenuation of endothelial dysfunction and modulating the mRNA expression of adenosine monophosphate-activated protein kinase (AMPK) and its downstream kinase liver kinase B1 (LKB1) in rats with diabetic nephropathy (DN). Diabetes was induced by a single intraperitoneal injection of streptozotocin (55 mg kg(-1)). Fenofibrate (100 mg kg(-1), p.o.) was given to diabetic rats daily for 12 weeks. Treatment with fenofibrate significantly improved the renal function as revealed by the significant reductions in urinary albumin excretion and serum levels of creatinine and urea, in addition to the significant increase in creatinine clearance compared with the diabetic control group. Hyperglycemia-induced oxidative damage was ameliorated by treatment with fenofibrate as indicated by the significantly increased levels of glutathione and catalase together with the significant decrease in lipid peroxidation. Administration of fenofibrate caused significant increases in renal nitric oxide (NO) production and mRNA expression of endothelial NO synthase (eNOS), AMPK and LKB1, reflecting improvement of endothelial function. Our results give further insights into the mechanisms underlying the protective role of fenofibrate in DN via modulation of AMPK, LKB1 and eNOS mRNA expression.
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Affiliation(s)
- Nawal M Al-Rasheed
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
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Shayman JA. Challenges and opportunities in the development of therapeutics for chronic kidney disease. Transl Res 2015; 165:482-7. [PMID: 25218118 DOI: 10.1016/j.trsl.2014.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 08/14/2014] [Indexed: 11/25/2022]
Affiliation(s)
- James A Shayman
- Nephrology Division, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Mich.
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Balakumar P, Varatharajan R, Nyo YH, Renushia R, Raaginey D, Oh AN, Akhtar SS, Rupeshkumar M, Sundram K, Dhanaraj SA. Fenofibrate and dipyridamole treatments in low-doses either alone or in combination blunted the development of nephropathy in diabetic rats. Pharmacol Res 2014; 90:36-47. [PMID: 25263930 DOI: 10.1016/j.phrs.2014.08.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Revised: 08/20/2014] [Accepted: 08/26/2014] [Indexed: 12/19/2022]
Abstract
Low-doses of fenofibrate and dipyridamole have pleiotropic renoprotective actions in diabetic rats. This study investigated their combined effect relative to their individual treatments and lisinopril in rats with diabetic nephropathy. Streptozotocin (55mg/kg, i.p., once)-administered diabetic rats were allowed for 10 weeks to develop nephropathy. Diabetic rats after 10 weeks developed nephropathy with discernible renal structural and functional changes as assessed in terms of increase in kidney weight to body weight ratio (KW/BW), and elevations of serum creatinine, urea and uric acid, which accompanied with elevated serum triglycerides and decreased high-density lipoproteins. Hematoxylin-eosin, periodic acid Schiff and Masson trichrome staining confirmed renal pathological changes in diabetic rats that included glomerular capsular wall distortion, mesangial cell expansion, glomerular microvascular condensation, tubular damage and degeneration and fibrosis. Low-dose fenofibrate (30mg/kg, p.o., 4 weeks) and low-dose dipyridamole (20mg/kg, p.o., 4 weeks) treatment either alone or in combination considerably reduced renal structural and functional abnormalities in diabetic rats, but without affecting the elevated glucose level. Fenofibrate, but not dipyridamole, significantly prevented the lipid alteration and importantly the uric acid elevation in diabetic rats. Lisinopril (5mg/kg, p.o., 4 weeks, reference compound), prevented the hyperglycemia, lipid alteration and development of diabetic nephropathy. Lipid alteration and uric acid elevation, besides hyperglycemia, could play key roles in the development of nephropathy. Low-doses of fenofibrate and dipyridamole treatment either alone or in combination markedly prevented the diabetes-induced nephropathy. Their combination was as effective as to their individual treatment, but not superior in preventing the development of diabetic nephropathy.
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Affiliation(s)
- Pitchai Balakumar
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia.
| | - Rajavel Varatharajan
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia
| | - Ying Hui Nyo
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia
| | - Raja Renushia
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia
| | - Devarajan Raaginey
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia
| | - Ann Nah Oh
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia
| | - Shaikh Sohrab Akhtar
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia
| | - Mani Rupeshkumar
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia
| | - Karupiah Sundram
- Pharmaceutical Chemistry Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia
| | - Sokkalingam A Dhanaraj
- Pharmaceutical Technology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia
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Kitada M, Kanasaki K, Koya D. Clinical therapeutic strategies for early stage of diabetic kidney disease. World J Diabetes 2014; 5:342-356. [PMID: 24936255 PMCID: PMC4058738 DOI: 10.4239/wjd.v5.i3.342] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 03/08/2014] [Accepted: 04/17/2014] [Indexed: 02/05/2023] Open
Abstract
Diabetic kidney disease (DKD) is the most common cause of chronic kidney disease, leading to end-stage renal disease and cardiovascular disease. The overall number of patients with DKD will continue to increase in parallel with the increasing global pandemic of type 2 diabetes. Based on landmark clinical trials, DKD has become preventable by controlling conventional factors, including hyperglycemia and hypertension, with multifactorial therapy; however, the remaining risk of DKD progression is still high. In this review, we show the importance of targeting remission/regression of microalbuminuria in type 2 diabetic patients, which may protect against the progression of DKD and cardiovascular events. To achieve remission/regression of microalbuminuria, several steps are important, including the early detection of microalbuminuria with continuous screening, targeting HbA1c < 7.0% for glucose control, the use of renin angiotensin system inhibitors to control blood pressure, the use of statins or fibrates to control dyslipidemia, and multifactorial treatment. Reducing microalbuminuria is therefore an important therapeutic goal, and the absence of microalbuminuria could be a pivotal biomarker of therapeutic success in diabetic patients. Other therapies, including vitamin D receptor activation, uric acid-lowering drugs, and incretin-related drugs, may also be promising for the prevention of DKD progression.
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Balakumar P, Sundram K, Dhanaraj SA. Dapagliflozin: Glucuretic action and beyond. Pharmacol Res 2014; 82:34-9. [DOI: 10.1016/j.phrs.2014.03.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Revised: 03/19/2014] [Accepted: 03/20/2014] [Indexed: 01/15/2023]
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Speeckaert MM, Vanfraechem C, Speeckaert R, Delanghe JR. Peroxisome proliferator-activated receptor agonists in a battle against the aging kidney. Ageing Res Rev 2014; 14:1-18. [PMID: 24503003 DOI: 10.1016/j.arr.2014.01.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Accepted: 01/24/2014] [Indexed: 12/19/2022]
Abstract
As aging is a complex phenomenon characterized by intraindividual and interindividual diversities in the maintenance of the homeostatic condition of cells and tissues, changes in renal function are not uniform and depend on associated diseases and environmental factors. Multiple studies have investigated the possible underlying mechanisms of age-related decline in kidney function. Evolutionary, molecular, cellular and systemic theories have been postulated to explain the primary disease independent age-related changes and adaptive responses. As peroxisome proliferator-activated receptors (PPARs) are involved in a broad spectrum of biological processes, PPAR activation might have an effect on the prevention of cell senescence. In this review, we will focus on the experimental and clinical evidence of PPAR agonists in a battle against the aging kidney.
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Affiliation(s)
| | | | | | - Joris R Delanghe
- Department of Clinical Chemistry, Ghent University Hospital, Gent, Belgium
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Ibrahim MA, El-Sheikh AAK, Khalaf HM, Abdelrahman AM. Protective effect of peroxisome proliferator activator receptor (PPAR)-α and -γ ligands against methotrexate-induced nephrotoxicity. Immunopharmacol Immunotoxicol 2014; 36:130-7. [PMID: 24521009 DOI: 10.3109/08923973.2014.884135] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
CONTEXT The anticancer drug methotrexate (MTX) may cause multi-organ toxicities, including nephrotoxicity. OBJECTIVE To investigate effects of peroxisome proliferator activator receptor (PPAR)-α and -γ agonists; fenofibrate (FEN) and pioglitazone (PIO), in MTX-induced nephrotoxicity in rats. METHODS Rats were given FEN or PIO (150 or 5 mg/kg/day, respectively) orally for 15 days. MTX was injected as a single dose of 20 mg/kg, i.p. at day 11 of experiment, with or without either PPAR agonists. RESULTS MTX induced renal toxicity, assessed by increase in serum urea and creatinine as well as histopathological alterations. MTX caused renal oxidative/nitrosative stress, indicated by decrease in GSH and catalase with increase in malondialdehyde and nitric oxide (NOx) levels. In addition, MTX increased renal level of the pro-inflammatory cytokine; tumor necrosis factor (TNF)-α and up-regulated the expression of both the inflammatory and apoptotic markers; NF-κB and caspase 3. Pre-administration of FEN or PIO to MTX-treated rats improved renal function and reversed oxidative/nitrosative parameters. Interestingly, pre-administration of PIO, but not FEN, decreased renal TNF-α level and NF-κB expression compared to MTX alone. Furthermore, PIO had more significant effect than FEN on reversing MTX-induced renal caspase 3 expression. DISCUSSION Both FEN and PIO conferred protection against MTX-induced nephrotoxicity through comparable amelioration of oxidative/nitrosative stress. FEN lacked any effect on TNF-α/NF-κB, which was reflected on its less improvement on renal histopathology and apoptosis. CONCLUSION At indicated dosage, PPAR-γ ligand; PIO shows better improvement of MTX-induced nephrotoxicity compared to PPAR-α ligand; FEN due to differential effect on TNF-α/NF-κB inflammatory pathway.
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Affiliation(s)
- Mohamed A Ibrahim
- Department of Pharmacology, Faculty of Medicine, Minia University , Minia , Egypt
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Jia Z, Sun Y, Yang G, Zhang A, Huang S, Heiney KM, Zhang Y. New Insights into the PPAR γ Agonists for the Treatment of Diabetic Nephropathy. PPAR Res 2014; 2014:818530. [PMID: 24624137 PMCID: PMC3927865 DOI: 10.1155/2014/818530] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Accepted: 12/16/2013] [Indexed: 02/07/2023] Open
Abstract
Diabetic nephropathy (DN) is a severe complication of diabetes and serves as the leading cause of chronic renal failure. In the past decades, angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs) based first-line therapy can slow but cannot stop the progression of DN, which urgently requests the innovation of therapeutic strategies. Thiazolidinediones (TZDs), the synthetic exogenous ligands of nuclear receptor peroxisome proliferator-activated receptor- γ (PPAR γ ), had been thought to be a promising candidate for strengthening the therapy of DN. However, the severe adverse effects including fluid retention, cardiovascular complications, and bone loss greatly limited their use in clinic. Recently, numerous novel PPAR γ agonists involving the endogenous PPAR γ ligands and selective PPAR γ modulators (SPPARMs) are emerging as the promising candidates of the next generation of antidiabetic drugs instead of TZDs. Due to the higher selectivity of these novel PPAR γ agonists on the regulation of the antidiabetes-associated genes than that of the side effect-associated genes, they present fewer adverse effects than TZDs. The present review was undertaken to address the advancements and the therapeutic potential of these newly developed PPAR γ agonists in dealing with diabetic kidney disease. At the same time, the new insights into the therapeutic strategies of DN based on the PPAR γ agonists were fully addressed.
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Affiliation(s)
- Zhanjun Jia
- Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing 210008, China
- Institute of Pediatrics, Nanjing Medical University, Nanjing, China
- Key Pediatric Laboratory of Nanjing City, Nanjing 210008, China
| | - Ying Sun
- Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing 210008, China
- Institute of Pediatrics, Nanjing Medical University, Nanjing, China
- Key Pediatric Laboratory of Nanjing City, Nanjing 210008, China
| | - Guangrui Yang
- Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Aihua Zhang
- Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing 210008, China
- Institute of Pediatrics, Nanjing Medical University, Nanjing, China
- Key Pediatric Laboratory of Nanjing City, Nanjing 210008, China
| | - Songming Huang
- Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing 210008, China
- Institute of Pediatrics, Nanjing Medical University, Nanjing, China
- Key Pediatric Laboratory of Nanjing City, Nanjing 210008, China
| | | | - Yue Zhang
- Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing 210008, China
- Institute of Pediatrics, Nanjing Medical University, Nanjing, China
- Key Pediatric Laboratory of Nanjing City, Nanjing 210008, China
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Abstract
BACKGROUND Early endothelial outgrowth cells (eEOCs) protect mice from acute kidney injury (AKI). Peroxisome proliferator-activated receptor-alpha (PPAR-α) has been shown to mediate renoprotective effects under different experimental conditions. The aim of the study was to investigate consequences of fibrate treatment of murine eEOCs in a cell-based therapeutic approach to AKI. METHODS Male C57/Bl6N mice, subjected to unilateral renal ischemia (40 min) post-uninephrectomy, were systemically injected with 0.5 × 10(6) untreated or fenofibrate (FF 1, 5, 10 or 50 μm)/clofibrate (CF 1 mm) pretreated syngeneic murine eEOCs. Renal function and morphology were analyzed 48 h later. Cellular consequences of eEOC treatment with fibrates (FF 1, 5, 10, 50 μm, CF 1 mm) were evaluated using different in vitro assays (direct cell migration, apoptosis/necrosis, ELISA studies). RESULTS Administration of untreated eEOCs did not protect mice from AKI. Injection of eEOCs treated with CF (1 mm) or FF 50 μm did not result in any protection from ischemia-induced renal dysfunction. In vitro analysis showed reduced cellular secretion of vasoprotective vascular endothelial growth factor (VEGF), an effect that was more pronounced with CF; FF increased percentages of apoptotic/necrotic eEOCs, and both substances failed to stimulate migration of cultured cells. With lower FF concentrations (1, 5, 10 μm) cell survival was increased and 10 μm FF stimulated VEGF secretion. In vivo administration of FF-treated eEOCs (10 μm) also did not result in any renoprotective effect. CONCLUSION PPAR-α activation using fibrates does not stimulate renoprotective effects of syngeneic murine eEOCs in ischemic AKI, although lower fibrate concentrations significantly activate eEOCs in vitro.
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Seok H, Cha BS. Refocusing Peroxisome Proliferator Activated Receptor-α: A New Insight for Therapeutic Roles in Diabetes. Diabetes Metab J 2013; 37:326-32. [PMID: 24199160 PMCID: PMC3816132 DOI: 10.4093/dmj.2013.37.5.326] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Although glucose-lowering treatment shows some risk lowering effects in cardiovascular diseases, risks of macrovascular and microvascular complications have still remained, and development of new therapeutic strategies is needed. Recent data have shown that peroxisome proliferator activated receptor-α (PPAR-α) plays a pivotal role in the regulation of lipid homeostasis, fatty acid oxidation, cellular differentiation, and immune response such as inflammation or vascularization related to diabetic complication. This review will re-examine the metabolic role of PPAR-α, summarize data from clinical studies on the effect of PPAR-α agonist in diabetes, and will discuss the possible therapeutic role of PPAR-α activation.
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Affiliation(s)
- Hannah Seok
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Bong Soo Cha
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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Kostapanos MS, Florentin M, Elisaf MS. Fenofibrate and the kidney: an overview. Eur J Clin Invest 2013; 43:522-531. [PMID: 23480615 DOI: 10.1111/eci.12068] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2013] [Accepted: 02/11/2013] [Indexed: 12/18/2022]
Abstract
BACKGROUND Fenofibrate has been used for the management of atherogenic dyslipidaemia for many years. Reports of fenofibrate-associated increases in serum creatinine (SCr) levels raised concerns regarding deleterious effects on renal function. DESIGN In this narrative review, we discuss available literature on the effect of fenofibrate on the kidney. RESULTS Most clinical studies showed a rapid (within weeks) raising effect of fenofibrate on SCr levels. This was often accompanied by declined estimated glomerular filtration rate. Risk predictors of this adverse effect might include increased age, impaired renal function and high-dose treatment. Also, the concomitant use of medications affecting renal hemodynamics (e.g. angiotensin-converting enzyme-inhibitors (ACEi) and angiotensin receptor blockers) may predispose to fenofibrate-associated increased SCr levels. Interestingly, SCr increases by fenofibrate were transient and reversible even without treatment discontinuation. Furthermore, fenofibrate was associated with a slower progression of renal function impairment and albuminuria in a long-term basis. Also, fenofibrate might be protective against pathological changes in diabetic nephropathy and hypertensive glomerulosclerosis. In this context, it is uncertain whether fenofibrate-associated increase in SCr levels mirrors true renal function deterioration. Several theories have been expressed. The most dominant one involved the inhibition of renal vasodilatory prostaglandins reducing renal plasma flow and glomerular pressure. Increased creatinine secretion or reduced creatinine clearance by fenofibrate was also suggested. These hypotheses should be settled by further studies. CONCLUSIONS Fenofibrate may not be a nephrotoxic drug. However, a close monitoring of SCr levels is relevant especially in high-risk patients. Increases in SCr levels ≥30% can impose treatment discontinuation.
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Affiliation(s)
- Michael S Kostapanos
- Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece
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Abstract
The most problematic issue in clinical nephrology is the relentless and progressive increase in patients with ESRD (end-stage renal disease) worldwide. The impact of diabetic nephropathy on the increasing population with CKD (chronic kidney disease) and ESRD is enormous. Three major pathways showing abnormality of intracellular metabolism have been identified in the development of diabetic nephropathy: (i) the activation of polyol and PKC (protein kinase C) pathways; (ii) the formation of advanced glycation end-products; and (iii) intraglomerular hypertension induced by glomerular hyperfiltration. Upstream of these three major pathways, hyperglycaemia is the major driving force of the progression to ESRD from diabetic nephropathy. Downstream of the three pathways, microinflammation and subsequent extracellular matrix expansion are common pathways for the progression of diabetic nephropathy. In recent years, many researchers have been convinced that the inflammation pathways play central roles in the progression of diabetic nephropathy, and the identification of new inflammatory molecules may link to the development of new therapeutic strategies. Various molecules related to the inflammation pathways in diabetic nephropathy include transcription factors, pro-inflammatory cytokines, chemokines, adhesion molecules, Toll-like receptors, adipokines and nuclear receptors, which are candidates for the new molecular targets for the treatment of diabetic nephropathy. Understanding of these molecular pathways of inflammation would translate into the development of anti-inflammation therapeutic strategies.
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Wang Y, Ye S, Hu Y, Zhao L, Zheng M. The effect of hydrochloride pioglitazone on urinary 8-hydroxy -deoxyguanosine excretion in type 2 diabetics. J Diabetes Complications 2013; 27:75-7. [PMID: 23021797 DOI: 10.1016/j.jdiacomp.2012.08.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2012] [Revised: 08/10/2012] [Accepted: 08/14/2012] [Indexed: 01/04/2023]
Abstract
OBJECTIVE To observe the effects of hydrochloride pioglitazone on urinary 8-hydroxy-deoxyguanosine (8OHdG) excretion in type 2 diabetics and explore its possible reno-protective mechanisms. METHODS Ninety-eight uncontrolled type 2 diabetics were assigned randomly into group DP (pioglitazone add-on) and group DS (sulfonylureas add-on). At the basal and after 12 weeks treatment, FBG, HbA1c, urinary 8-OHdG, urinary albumin(ALB) and urinary creatinine (Cr) were determined, respectively. RESULTS Compared with pre-treatment, FBG, HbA1c and urinary 8-OHdG /Cr ratio(U8CR) were all obviously decreased in both therapy groups; urinary albumin/urinary creatinine ratio(UACR) markedly decreased in group DP (P<0.01), while slightly decreased in group DS (P>0.05) after twelve weeks of observation. After 12-week treatment, UACR and U8CR in group DP were significantly lower than those in group DS (both P<0.05) without no marked difference in FBG and HbA1c between group DP and group DS. Meanwhile, U8CR had positive correlation with UACR (r=0.755, P<0.01). CONCLUSION Pioglitazone can decrease urinary 8-OHdG excretion and lighten oxidative stress in vivo in type 2 diabetics, which may play a protective role for the kidney damage.
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Affiliation(s)
- Yuefen Wang
- Department of Endocrinology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, PR China
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Kadian S, Mahadevan N, Balakumar P. Differential effects of low-dose fenofibrate treatment in diabetic rats with early onset nephropathy and established nephropathy. Eur J Pharmacol 2012; 698:388-96. [PMID: 23085026 DOI: 10.1016/j.ejphar.2012.10.012] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2012] [Revised: 09/28/2012] [Accepted: 10/06/2012] [Indexed: 01/13/2023]
Abstract
We have previously shown that low-dose fenofibrate treatment has an ability to prevent diabetes-induced nephropathy in rats. We investigated here the comparative pre- and post-treatment effects of low-dose fenofibrate (30 mg/kg/day p.o.) in diabetes-induced onset of nephropathy. Rats were made diabetics by single administration of streptozotocin (STZ, 55 mg/kg i.p.). The development of diabetic nephropathy was assessed biochemically and histologically. Moreover, lipid profile and renal oxidative stress were assessed. Diabetic rats after 8 weeks of STZ-administration developed apparent nephropathy by elevating serum creatinine, blood urea nitrogen and microproteinuria, and inducing glomerular-capsular wall distortion, mesangial expansion and tubular damage and renal oxidative stress. Fenofibrate (30 mg/kg/day p.o., 4 weeks) pretreatment (4 weeks after STZ-administration) markedly prevented diabetes-induced onset of diabetic nephropathy, while the fenofibrate (30 mg/kg/day p.o., 4 weeks) post-treatment (8 weeks after STZ-administration) was less-effective. However, both pre-and post fenofibrate treatments were effective in preventing diabetes-induced renal oxidative stress and lipid alteration in diabetic rats though the pretreatment was slightly more effective. Conversely, both pre-and post fenofibrate treatments did not alter elevated glucose levels in diabetic rats. It may be concluded that diabetes-induced oxidative stress and lipid alteration, in addition to a marked glucose elevation, play a detrimental role in the onset of nephropathy in diabetic rats. The pretreatment with low-dose fenofibrate might be a potential therapeutic approach in preventing the onset of nephropathy in diabetic subjects under the risk of renal disease induction. However, low-dose fenofibrate treatment might not be effective in treating the established nephropathy in diabetic subjects.
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Affiliation(s)
- Supriya Kadian
- Cardiovascular Pharmacology Division, Department of Pharmacology, Rajendra Institute of Technology and Sciences, Sirsa 125 055, India
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The combined strategy with PPARα agonism and AT1 receptor antagonism is not superior relative to their individual treatment approach in preventing the induction of nephropathy in the diabetic rat. Pharmacol Res 2012; 66:349-56. [DOI: 10.1016/j.phrs.2012.07.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2012] [Revised: 07/02/2012] [Accepted: 07/03/2012] [Indexed: 12/15/2022]
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