马兜铃酸
肾病
肾
下调和上调
肾毒性
基因敲除
基因剔除小鼠
急性肾损伤
药理学
癌症研究
医学
化学
细胞凋亡
内分泌学
内科学
生物
受体
生物化学
基因
糖尿病
遗传学
作者
Yi Wang,Zhigang Wang,Zhengping Wu,Menglin Chen,Dong Dong,Pei Yu,Danyi Lu,Baojian Wu
标识
DOI:10.1016/j.bcp.2021.114807
摘要
The molecular events underlying aristolochic acid (AA) nephropathy are poorly understood, and specific therapies for treatment of AA nephropathy are still lacking. Here we aimed to investigate a potential role of REV-ERBα and ferroptosis in renal injury induced by aristolochic acid I (AAI), a typical AA. The regulatory effects of REV-ERBα on AAI-induced renal injury were determined using kidney-specific Rev-erbα knockout mice. Ferroptosis was assessed based on measurements of iron, GSH, and GPX4. Targeted antagonism of REV-ERBα to alleviate AAI-induced renal injury and ferroptosis was assessed using the small molecule antagonist SR8278. mRNAs and proteins were quantified by qPCR and Western blotting, respectively. We first showed that REV-ERBα was upregulated and its target BMAL1 was downregulated in the kidney of mice with AAI nephropathy. Upregulation of REV-ERBα protein was confirmed in aristolactam I (ALI, a nephrotoxic metabolite of AAI)-treated mRTECs. We also observed enhanced ferroptosis (known to be regulated by REV-ERBα) in mice with AAI nephropathy and in ALI-treated mRTECs. Kidney-specific knockout of Rev-erbα reduced the sensitivity of mice to AAI-induced ferroptosis and renal injury. Furthermore, knockdown of Rev-erbα by siRNA or SR8278 (a REV-ERBα antagonist) treatment attenuated ALI-induced ferroptosis in mRTECs. Moreover, REV-ERBα antagonism by SR8278 alleviated ferroptosis and renal injury caused by AAI in mice. In conclusion, we identify REV-ERBα as a regulator of AAI-induced renal injury via promoting ferroptosis. Targeting REV-ERBα may represent a promising approach for management of AAI nephropathy.
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