Beneficial effects of bardoxolone methyl, an Nrf2 activator, on crush-related acute kidney injury in rats.

Abstract

The purpose of this study was to investigate the effects of bardoxolone methyl (BM), a nuclear factor erythroid 2-related factor 2 (Nrf2) activator, on acute kidney injury in a rat model of crush syndrome model. Sixty-four rats were separated equally into eight groups, sham (sterile saline ip), crush, crush + vehicle (DMSO ip), and crush + BM (10mg/kg ip) (n = 8). All groups were also divided as 3 and 24h after decompression. Crush injury was induced by 6h of direct compression to both hind limbs of the rats with blocks weighing 3.6kg on each side, followed by 3 and 24h of decompression. Kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), tumor necrotizing factor-α (TNF-α), transforming growth factor-β1 (TGF-β1) concentrations, tissue total oxidant status (TOS) and total antioxidant status (TAS) were measured in the kidneys. Serum creatine kinase (CK), blood urea nitrogen (BUN) and creatinine concentrations were also measured. Glomerular and tubular structures were examined histopathologically. Bcl-2 was measured using immunohistochemistry. Apoptosis was assessed using the TUNEL method. BM treatment reduced KIM-1, NGAL, TNF-α, TGF-β1, TOS concentrations, and increased TAS concentrations in the kidneys 3 and 24h after decompression. Serum CK, BUN and creatinine concentrations were also reduced with BM. BM treatment decreased apoptosis in crush-related AKI. The Nrf2 activator BM reversed the crush-induced changes in the experimental rats. BM treatment prevented the progression of crush-related AKI in rats possibly through its cytoprotective effects of being an antioxidant, anti-inflammatory and anti-apoptotic agent.