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

BACKGROUND

Studies have suggested that estrogens may protect mice from AKI. Estrogen sulfotransferase (, or EST) plays an important role in estrogen homeostasis by sulfonating and deactivating estrogens, but studies on the role of in AKI are lacking.

METHODS

We used the renal ischemia-reperfusion model to investigate the role of in AKI. We subjected wild-type mice, knockout mice, and knockout mice with liver-specific reconstitution of 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 inhibitor triclosan to determine the effect of pharmacologic inhibition of on AKI.

RESULTS

AKI induced the expression of in a tissue-specific and sex-specific manner. It induced expression of in the liver in both male and female mice, but induction in the kidney occurred only in male mice. Genetic knockout or pharmacologic inhibition of 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 in knockout mice abolished the protection in male mice but not in female mice, indicating that 's effect on AKI was also tissue-specific and sex-specific.

CONCLUSIONS

appears to have a novel function in the pathogenesis of AKI. Our findings suggest that inhibitors of might have therapeutic utility in the clinical management of AKI.