title: Amelioration of Renal Inflammation, Endoplasmic Reticulum Stress and Apoptosis Underlies the Protective Effect of Low Dosage of Atorvastatin in Gentamicin-Induced Nephrotoxicity.
abstract: Gentamicin is a commonly used aminoglycoside antibiotic. However, its therapeutic use is limited by its nephrotoxicity. The mechanisms of gentamicin-induced nephrotoxicity are principally from renal inflammation and oxidative stress. Since atorvastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, exerts lipid-lowering effects, antioxidant, anti-inflammatory as well as anti-apoptotic effects, this study aimed to investigate the protective effects of atorvastatin against gentamicin-induced nephrotoxicity. Male Sprague Dawley rats were used and nephrotoxicity was induced by intraperitoneal injection of gentamicin, 100 mg/kg/day, for 15 days. Atorvastatin, 10 mg/kg/day, was administered by orally gavage 30 min before gentamicin injection on day 1 to 15 (pretreatment) or on day 10 to15 (delayed treatment). For only atorvastatin treatment group, it was given on day 1 to 15. At the end of the experiment, kidney weight, blood urea nitrogen and serum creatinine as well as renal inflammation (NF-κB, TNFαR1, IL-6 and iNOS), renal fibrosis (TGFβ1), ER stress (calpain, GRP78, CHOP, and caspase 12) and apoptotic markers (cleaved caspase-3, Bax, and Bcl-2) as well as TUNEL assay were determined. Gentamicin-induced nephrotoxicity was confirmed by marked elevations in serum urea and creatinine, kidney hypertrophy, renal inflammation, fibrosis, ER stress and apoptosis and attenuation of creatinine clearance. Atorvastatin pre and delayed treatment significantly improved renal function and decreased renal NF-κB, TNFαR1, IL-6, iNOS and TGFβ1 expressions. They also attenuated calpain, GRP78, CHOP, caspase 12, Bax, and increased Bcl-2 expressions in gentamicin-treated rat. These results indicate that atorvastatin treatment could attenuate gentamicin-induced nephrotoxicity in rats, substantiated by the reduction of inflammation, ER stress and apoptosis. The effect of atorvastatin in protecting from renal damage induced by gentamicin seems to be more effective when it beginning given along with gentamicin or pretreatment.
authors.affiliation: Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Krit
authors.initials: K
authors.lastname: Jaikumkao
authors.affiliation: Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Anchalee
authors.initials: A
authors.lastname: Pongchaidecha
authors.affiliation: Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: La-Ongdao
authors.initials: LO
authors.lastname: Thongnak
authors.affiliation: Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.|School of Medicine, Mae Fah Luang University, Chiang Rai, Thailand.
authors.forename: Keerati
authors.initials: K
authors.lastname: Wanchai
authors.affiliation: Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Phatchawan
authors.initials: P
authors.lastname: Arjinajarn
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Varanuj
authors.initials: V
authors.lastname: Chatsudthipong
authors.affiliation: Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.|Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Nipon
authors.initials: N
authors.lastname: Chattipakorn
authors.affiliation: Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Anusorn
authors.initials: A
authors.lastname: Lungkaphin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000069059:Atorvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D001806:Blood Urea Nitrogen; D053454:Caspase 12 / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005839:Gentamicins / Q000633:toxicity*; D006360:Heat-Shock Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009393:Nephritis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D005839:Gentamicins; D006360:Heat-Shock Proteins; D015850:Interleukin-6; D016328:NF-kappa B; D020011:Protective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D053773:Transforming Growth Factor beta1; D051028:bcl-2-Associated X Protein; D000069059:Atorvastatin; D003404:Creatinine; D052247:Nitric Oxide Synthase Type II; D053454:Caspase 12