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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.

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1Oxidative stress-mediated apoptosis of renal tubular cells is a major pathology 2 of gentamicin-induced nephrotoxicity which is one of the prevailing causes of acute 3 renal failure. Pinocembrin is a major flavonoid found in rhizomes of fingerroot 4 (Boesenbergia pandurata). It has pharmacological and biological activities including 5 antimicrobial, anti-inflammatory, and antioxidant effects. Preclinical studies have 6 suggested that pinocembrin protects rat brain and heart against oxidation and apoptosis 7 induced by ischemia-reperfusion model. The aim of the current study was to investigate 8 the mechanisms of renoprotection elicited by pinocembrin in gentamicin-induced 9 nephrotoxicity. Nephrotoxic rats were induced by intraperitoneal injection (i.p) of 10 gentamicin and pinocembrin was administered via i.p. 30 min before gentamicin 11 treatment for 10 days. Gentamicin-induced nephrotoxicity was indicated by the reduced 12 renal function and renal Oat3 function and expression. Gentamicin treatment also 13 stimulated Nrf2, HO-1, and NQO1 and the pro-apoptotic protein, Bax and caspase-3, 14 concomitant with the attenuation of Bcl-XL expressions in the renal cortical tissues. 15Pinocembrin pretreatment improved renal function, renal Oat3 function, reduced 16 oxidative stress and apoptotic conditions. These findings indicate that pinocembrin has 17 a protective effect against gentamicin-induced nephrotoxicity which may be due in part 18 to its antioxidant and anti-apoptotic effects, subsequently leading to improved renal 19 function. 20 21