title: Renoprotective Effects of Aldose Reductase Inhibitor Epalrestat against High Glucose-Induced Cellular Injury.
abstract: Diabetic nephropathy (DN) is the leading cause of end stage renal disease worldwide. Increased glucose flux into the aldose reductase (AR) pathway during diabetes was reported to exert deleterious effects on the kidney. The objective of this study was to investigate the renoprotective effects of AR inhibition in high glucose milieu in vitro. Rat renal tubular (NRK-52E) cells were exposed to high glucose (30 mM) or normal glucose (5 mM) media for 24 to 48 hours with or without the AR inhibitor epalrestat (1μM) and assessed for changes in Akt and ERK1/2 signaling, AR expression (using western blotting), and alterations in mitochondrial membrane potential (using JC-1 staining), cell viability (using MTT assay), and cell cycle. Exposure of NRK-52E cells to high glucose media caused acute activation of Akt and ERK pathways and depolarization of mitochondrial membrane at 24 hours. Prolonged high glucose exposure (for 48 hours) induced AR expression andG1 cell cycle arrest and decreased cell viability (84% compared to control) in NRK-52E cells. Coincubation of cells with epalrestat prevented the signaling changes and renal cell injury induced by high glucose. Thus, AR inhibition represents a potential therapeutic strategy to prevent DN.
authors.affiliation: College of Pharmacy, Qatar University, P.O. Box 2713, Doha, Qatar.
authors.forename: Heba
authors.identifier: 0000-0002-5972-9512
authors.initials: H
authors.lastname: El Gamal
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: Ali Hussein
authors.initials: AH
authors.lastname: Eid
authors.affiliation: College of Pharmacy, Qatar University, P.O. Box 2713, Doha, Qatar.
authors.forename: Shankar
authors.identifier: 0000-0002-2023-7705
authors.initials: S
authors.lastname: Munusamy
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D051381:Rats; D012236:Rhodanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D053778:Thiazolidines / Q000008:administration & dosage*
chemical_list: D004791:Enzyme Inhibitors; D053778:Thiazolidines; C038131:epalrestat; D012236:Rhodanine; D000449:Aldehyde Reductase; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose