Bardoxolone methyl attenuates acetaminophen-induced acute kidney injury by suppressing oxidative stress, inflammation and apoptosis

Abstract

Aim: Nuclear factor erythroid 2-related factor 2 (Nrf2) plays an important role in attenuating several oxidative stress and inflammation-induced diseases, including acute kidney injury (AKI). Bardoxolone methyl (BM) is one of the most potent Nrf2 activator. The aim of this study was to investigate the renoprotective effect of BM against acetaminophen (APAP)-induced AKI in rats. Materials and Methods: Forty-two rats were equally divided into six groups: control (saline), vehicle (sesame oil), APAP, APAP+N-acetylcysteine (NAC) (160 mg/kg), APAP+BM (5 mg/kg), and APAP+BM (10 mg/kg). Kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), tumour necrosis factor-α (TNF-α) levels, tissue total oxidant status (TOS) and total antioxidant status (TAS) were measured in the kidneys. Glomerular and tubular structures were examined histopathologically. Caspase-3 was assessed by immunohistochemistry for apoptosis. Results: APAP caused severe nephrotoxicity as evidenced by increases in KIM-1, NGAL, TNF-α, oxidative stress and apoptosis in the kidney with histopathological chamges. BM dose-dependently reduced APAP-induced AKI, including oxidative damage, histopathological lesions, and apoptotic changes in the kidney. BM also attenuated KIM-1, NGAL and TNF-α levels in the kidney. Conclusion: BM has demonstrated therapeutic effects against APAP-induced AKI by enhancing the antioxidant system, modulating inflammatory cytokines and inhibiting apoptosis in rat kidney.