Inhibition of Estrogen Sulfotransferase (SULT1E1/EST) Ameliorates Ischemic Acute Kidney Injury in Mice
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Authors: Barbosa, Anne C. Silva; Zhou, Dong; Xie, Yang; Choi, You-Jin; Tung, Hung-Chun; Chen, Xinyun; Xu, Meishu; Gibbs, Robert B.; Poloyac, Samuel M.; Liu, Silvia; Yu, Yanping; Luo, Jianhua; Liu, Youhua; Xie, Wen
Significance Statement 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 of SULT1E1?s role in AKI are lacking. Using the ischemia-reperfusion model of AKI, the authors demonstrated that genetic ablation or pharmacologic inhibition of Sult1e1 can mitigate AKI in both male and female mice in a sex hormone-independent manner. A gene profiling analysis indicated that the renoprotective effect was associated with increased vitamin D receptor signaling. Liver-specific reconstitution of Sult1e1 resensitizes male Sult1e1 knockout mice to AKI, indicating that liver Sult1e1is required for ischemic AKI in males. These findings suggest that pharmacologic inhibition of SULT1E1 might represent a novel approach for clinical management of AKI. Background 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. Methods 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. Results 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. ConclusionsSULT1E1 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.
Triclosan disrupts immune cell function by depressing Ca2+ influx following acidification of the cytoplasm
TOXICOLOGY AND APPLIED PHARMACOLOGY
Authors: Sangroula, Suraj; Vasquez, Alan Y. Baez; Raut, Prakash; Obeng, Bright; Shim, Juyoung K.; Bagley, Grace D.; West, Bailey E.; Burnell, John E.; Kinney, Marissa S.; Potts, Christian M.; Weller, Sasha R.; Kelley, Joshua B.; Hess, Samuel T.; Gosse, Julie A.
Triclosan (TCS) is an antimicrobial agent that was effectively banned by the FDA from hand soaps in 2016, hospital soaps in 2017, and hand sanitizers in 2019; however, TCS can still be found in a few products. At consumer-relevant, non-cytotoxic doses, TCS inhibits the functions of both mitochondria and mast cells, a ubiquitous cell type. Via the store-operated Ca2+ entry mechanism utilized by many immune cells, mast cells undergo antigen-stimulated Ca2+ influx into the cytosol, for proper function. Previous work showed that TCS inhibits Ca2+ dynamics in mast cells, and here we show that TCS also inhibits Ca2+ mobilization in human Jurkat T cells. However, the biochemical mechanism behind the Ca2+ dampening has yet to be elucidated. Three-dimensional super-resolution microscopy reveals that TCS induces mitochondrial swelling, in line with and extending the previous finding of TCS inhibition of mitochondrial membrane potential via its proton ionophoric activity. Inhibition of plasma membrane potential (PMP) by the canonical depolarizer gramicidin can inhibit mast cell function. However, use of the genetically encoded voltage indicators (GEVIs) ArcLight (pH sensitive) and ASAP2 (pH-insensitive), indicates that TCS does not disrupt PMP. In conjunction with data from a plasma membrane-localized, pH-sensitive reporter, these results indicate that TCS, instead, induces cytosolic acidification in mast cells and T cells. Acidification of the cytosol likely inhibits Ca2+ influx by uncoupling the STIM1/ORAI1 interaction that is required for opening of plasma membrane Ca2+ channels. These results provide a mechanistic explanation of TCS disruption of Ca2+ influx and, thus, of immune cell function.