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

Abstract

Studies have suggested that estrogens may protect mice from AKI. Estrogen sulfotransferase (<i>SULT1E1</i>, or EST) plays an important role in estrogen homeostasis by sulfonating and deactivating estrogens, but studies on the role of <i>SULT1E1</i> in AKI are lacking. We used the renal ischemia-reperfusion model to investigate the role of <i>SULT1E1</i> in AKI. We subjected wild-type mice, <i>Sult1e1</i> knockout mice, and <i>Sult1e1</i> knockout mice with liver-specific reconstitution of <i>SULT1E1</i> 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 <i>SULT1E1</i> inhibitor triclosan to determine the effect of pharmacologic inhibition of <i>SULT1E1</i> on AKI. AKI induced the expression of <i>Sult1e1</i> in a tissue-specific and sex-specific manner. It induced expression of <i>Sult1e1</i> in the liver in both male and female mice, but <i>Sult1e1</i> induction in the kidney occurred only in male mice. Genetic knockout or pharmacologic inhibition of <i>Sult1e1</i> 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 <i>SULT1E1</i> in <i>Sult1e1</i> knockout mice abolished the protection in male mice but not in female mice, indicating that <i>Sult1e1</i>'s effect on AKI was also tissue-specific and sex-specific. <i>SULT1E1</i> appears to have a novel function in the pathogenesis of AKI. Our findings suggest that inhibitors of <i>SULT1E1</i> might have therapeutic utility in the clinical management of AKI.