title: Atorvastatin improves renal organic anion transporter 3 and renal function in gentamicin-induced nephrotoxicity in rats.
abstract: What is the central question of this study? This study was designed to determine the renoprotective effects of atorvastatin treatment in an experimental model of gentamicin-induced nephrotoxicity through modulating the Nrf2 pathway by decreasing the oxidative stress. What is the main finding and its importance? Atorvastatin exerts a nephroprotective effect by attenuating oxidative stress, protecting renal function and renal organic anion transporter 3 function from the effects of gentamicin. Atorvastatin might protect the tissues via its antioxidant property and by modulating the antioxidant enzymes through the Nrf2 signalling pathway, which may be the underlying mechanisms of these protective effects. Recent evidence demonstrates that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, exert not only lipid-lowering effects but also antioxidant, anti-inflammatory and anti-apoptotic effects. Nephrotoxicity, a serious side-effect of gentamicin, is related to an increase in reactive oxygen species in the kidney. This study was designed to determine the renoprotective effects of atorvastatin treatment in an experimental model of gentamicin-induced nephrotoxicity. Male Sprague-Dawley rats were used. Nephrotocixity was induced by i.p. injection of gentamicin, 100 mg kg(-1)  day(-1) , for 15 days. Atorvastatin, 10 mg kg(-1)  day(-1) , was administered by gavage 30 min before gentamicin injection (pretreatment) for 15 days or only on days 10-15 (post-treatment). Renal function and renal organic anion transporter 3 (Oat3) function and expression were examined. Gentamicin-treated rats demonstrated impaired renal function by attenuation of creatinine clearance and increased oxidative stress. Gentamicin treatment also decreased renal Oat3 function and expression as shown by decreased [(3) H]estrone sulfate uptake into renal cortical slices and decreased expression. The protein expressions of protein kinase C, Nrf2, NAD(P)H:quinone oxidoreductase 1, haeme oxygenase 1 and glutamate-cysteine ligase were markedly increased in gentamicin-treated rats, indicating the increase in oxidative stress. Administration of atorvastatin improved renal function and alleviated oxidative stress, and atorvastatin pretreatment had a greater ability to decrease oxidative stress than atorvastatin post-treatment. These effects helped to preserve renal function and Oat3 function and expression. These results indicate that atorvastatin has a renoprotective effect against gentamicin-induced nephrotoxicity by decreasing overoxidation in the kidney, and might be used in conjunction with gentamicin to protect against renal damage.
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: Cardiac Electrophysiology Research and Training Center, Department of Physiology, 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 Science, Mahidol University, Bangkok, Thailand.
authors.forename: Varanuj
authors.initials: V
authors.lastname: Chatsudthipong
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, The University of Phayao, Phayao, Thailand.
authors.forename: Sasivimon
authors.initials: S
authors.lastname: Promsan
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 Medicine, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Anusorn
authors.initials: A
authors.lastname: Lungkaphin
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000069059:Atorvastatin / Q000494:pharmacology*; D005839:Gentamicins / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D005839:Gentamicins; D029362:Organic Anion Transporters, Sodium-Independent; D017382:Reactive Oxygen Species; C114338:organic anion transport protein 3; D000069059:Atorvastatin