Inhibition of Estrogen Sulfotransferase (SULT1E1/EST) Ameliorates Ischemic Acute Kidney Injury in Mice.

Anne C Silva Barbosa, Dong Zhou, Yang Xie, You-Jin Choi, Hung-Chun Tung, Xinyun Chen, Meishu Xu, Robert B Gibbs, Samuel M Poloyac, Silvia Liu, Yanping Yu, Jianhua Luo, Youhua Liu, Wen Xie

Journal of the American Society of Nephrology : JASN 2020 Jul

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Studies have suggested that estrogens may protect mice from AKI. Estrogen sulfotransferase (SULT1E1, or EST) plays an important role in estrogen homeostasis by sulfonating and deactivating estrogens, but studies on the role of SULT1E1 in AKI are lacking. We used the renal ischemia-reperfusion model to investigate the role of SULT1E1 in AKI. We subjected wild-type mice, Sult1e1 knockout mice, and Sult1e1 knockout mice with liver-specific reconstitution of SULT1E1 expression to bilateral renal ischemia-reperfusion or sham surgery, either in the absence or presence of gonadectomy. We assessed relevant biochemical, histologic, and gene expression markers of kidney injury. We also used wild-type mice treated with the SULT1E1 inhibitor triclosan to determine the effect of pharmacologic inhibition of SULT1E1 on AKI. AKI induced the expression of Sult1e1 in a tissue-specific and sex-specific manner. It induced expression of Sult1e1 in the liver in both male and female mice, but Sult1e1 induction in the kidney occurred only in male mice. Genetic knockout or pharmacologic inhibition of Sult1e1 protected mice of both sexes from AKI, independent of the presence of sex hormones. Instead, a gene profiling analysis indicated that the renoprotective effect was associated with increased vitamin D receptor signaling. Liver-specific transgenic reconstitution of SULT1E1 in Sult1e1 knockout mice abolished the protection in male mice but not in female mice, indicating that Sult1e1's effect on AKI was also tissue-specific and sex-specific. SULT1E1 appears to have a novel function in the pathogenesis of AKI. Our findings suggest that inhibitors of SULT1E1 might have therapeutic utility in the clinical management of AKI. Copyright © 2020 by the American Society of Nephrology.

Citation

Anne C Silva Barbosa, Dong Zhou, Yang Xie, You-Jin Choi, Hung-Chun Tung, Xinyun Chen, Meishu Xu, Robert B Gibbs, Samuel M Poloyac, Silvia Liu, Yanping Yu, Jianhua Luo, Youhua Liu, Wen Xie. Inhibition of Estrogen Sulfotransferase (SULT1E1/EST) Ameliorates Ischemic Acute Kidney Injury in Mice. Journal of the American Society of Nephrology : JASN. 2020 Jul;31(7):1496-1508