title: Bardoxolone methyl (BARD) ameliorates aristolochic acid (AA)-induced acute kidney injury through Nrf2 pathway.
abstract: 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.
authors: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Nephrology, Ministry of Health, Guangzhou 510080, China.
authors: Juan
authors: J
authors: Wu
authors: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Nephrology, Ministry of Health, Guangzhou 510080, China.
authors: Xinhui
authors: X
authors: Liu
authors: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Nephrology, Ministry of Health, Guangzhou 510080, China.
authors: Jinjin
authors: J
authors: Fan
authors: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors: Wenfang
authors: W
authors: Chen
authors: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Nephrology, Ministry of Health, Guangzhou 510080, China.
authors: Juan
authors: J
authors: Wang
authors: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Nephrology, Ministry of Health, Guangzhou 510080, China.
authors: Youjia
authors: Y
authors: Zeng
authors: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Nephrology, Ministry of Health, Guangzhou 510080, China.
authors: Xiaorang
authors: X
authors: Feng
authors: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Nephrology, Ministry of Health, Guangzhou 510080, China.
authors: Xueqing
authors: X
authors: Yu
authors: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Nephrology, Ministry of Health, Guangzhou 510080, China. Electronic address: yangxsysu@126.com.
authors: Xiao
authors: X
authors: Yang
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D000818:Animals; D034341:Aristolochic Acids; D003451:Cryoprotective Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D008810:Mice, Inbred C57BL; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D034341:Aristolochic Acids; D003451:Cryoprotective Agents; D051267:NF-E2-Related Factor 2; D009828:Oleanolic Acid; C000228:aristolochic acid I; C445068:bardoxolone methyl; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human
keywords: Acute kidney injury; Aristolochic acid; Bardoxolone methyl; Heme oxygenase-1; NAD(P)H quinone oxidoreductase-1; Nuclear factor erythroid 2-related factor 2