Protective Effect of Celastrol on Gentamicin-induced Nephrotoxicity in Mice

Abstract

Background and Objectives: Gentamicin is an aminoglycoside antibiotic used to cure serious bacterial infections, although its usefulness is restricted due to the risk of nephrotoxicity. Celastrol is an active component of the Chinese medicine Tripterygium wilfordii, which has been demonstrated to be a potent anticancer agent in preclinical studies of cancer and inflammatory disorders. This study was aimed to investigate the effect of celastrol on gentamicin nephrotoxicity in mice and to explore the underlying mechanisms involved. Materials and Methods: Serum creatinine and blood urea-nitrogen concentrations, oxidative stress, inflammatory cytokines and histopathological changes of kidney tissues were monitored. Nephrotoxicity was detected after 50 mg kg(-1) daily dose of gentamicin intraperitoneal injection (IP) for 7 consecutive days. Mice were randomly divided into 5 groups. Group 1 received normal saline containing 5\% dimethyl sulfoxide, IP, at the same volume as the drugs received by other groups. Group 2 received gentamicin (50 mg/kg/day, IP). Groups 3 and 4th received gentamicin (50 mg kg(-1), IP) with celastrol (1 or 5 mg/kg/day, IP, respectively), celastrol was given 30 min before the gentamicin injection. Finally, group-5 received celastrol only (5 mg kg(-1), IP). Results: Celastrol significantly ameliorated gentamicin-induced elevation of serum creatinine, blood urea nitrogen and uric acid. It significantly reduced renal tissue malondialdehyde and restored activity of renal glutathione and superoxide dismutase. Moreover, it reduced TNF-alpha, IL-6, IL-beta 1 and NF-kappa Bp65 and partially recovered cellular damage, including distorted glomerular capillaries and tubular dilation with epithelial atrophy corresponding with dosage level. Conclusion: Celastrol could protect against gentamicin-induced acute kidney injury, possibly through suppressing oxidative stress and pro-inflammatory biomarkers and improving renal functional disturbances.