Bardoxolone methyl (BARD) is an
antioxidant modulator that acts through induction of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. This study aimed to investigate the role of BARD in protecting kidneys from
aristolochic acid (AA)-induced
acute kidney injury (AKI). Male C57BL/6 mice received intraperitoneal (i.p.)
injections of
aristolochic acid I (AAI) (5mg/kg/day) for 5 days to produce acute AA nephropathy (AAN) model. BARD (10mg/kg/day, i.p.) was applied for 7 consecutive days, starting 2 days prior to AAI administration. The mice in the AA group showed AKI as evidenced by worsening kidney function evaluated by blood
urea nitrogen (BUN) and serum
creatinine (SCr) levels, and severe tubulointerstitial injury marked by massive tubule
necrosis in kidney tissues. BARD significantly reduced BUN and SCr levels which were elevated by AAI. Additionally, AAI-induced histopathological renal damage was ameliorated by BARD. Furthermore, the expression of Nrf2 was reduced, and its repressor
Kelch-like ECH-associated protein 1 (Keap1) was increased significantly, whereas
heme oxygenase-1 (HO-1) was upregulated and
NAD(P)H
quinone oxidoreductase-1 (NQO1) was barely increased in the cytoplasm of tubules in kidneys
after treatment with AAI. BARD significantly upregulated renal Nrf2, NQO1 and HO-1 expression and downregulated Keap1 expression compared with those in the AA group. Moreover, it was found that Nrf2 was expressed both in the cytoplasm and nuclear of glomeruli and tubules, whereas NQO1 and HO-1 were localized in the cytoplasm of tubules only. In conclusion, AA-induced
acute renal injury was associated with impaired Nrf2 activation and expression of its downstream target genes in renal tissues. BARD prevented renal damage induced by AAI, and this renoprotective effect may be exerted by activating the Nrf2 signaling pathway and increasing expression of the downstream target genes.