{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T03:38:09Z","timestamp":1761709089235},"reference-count":39,"publisher":"American Physiological Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Renal Physiology"],"published-print":{"date-parts":[[2015,8,1]]},"abstract":"<jats:p>ANG II type 1 receptor blockade (AT<jats:sub>1<\/jats:sub>R-BLK) is used extensively to slow down the progression of proteinuric kidney diseases. We hypothesized that AT<jats:sub>1<\/jats:sub>R-BLK provides podocyte protection through regulation of silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) and vitamin D receptor (VDR) expression under adverse milieus such as high glucose and human immunodeficiency virus infection. Both AT<jats:sub>1<\/jats:sub>R-BLK and VDR agonists (VDAs) stimulated VDR complex formation that differed not only in their composition but also in their functionality. AT<jats:sub>1<\/jats:sub>R-BLK-induced VDR complexes contained predominantly unliganded VDR, SMRT, and phosphorylated histone deacetylase 3, whereas VDA-VDR complexes were constituted by liganded VDR and CREB-binding protein\/p300. AT<jats:sub>1<\/jats:sub>R-BLK-induced complexes attenuated podocyte acetyl-histone 3 levels as well as cytochrome P-450 family 24A1 expression, thus indicating their deacetylating and repressive properties. On the other hand, VDA-VDR complexes not only increased podocyte acetyl-histone 3 levels but also enhanced cytochrome P-450 family 24A1 expression, thus suggesting their acetylating and gene activation properties. AT<jats:sub>1<\/jats:sub>R-BLK- induced podocyte SMRT inhibited expression of the proapoptotic gene BAX through downregulation of Wip1 and phosphorylation of checkpoint kinase 2 in high-glucose milieu. Since SMRT-depleted podocytes lacked AT<jats:sub>1<\/jats:sub>R-BLK-mediated protection against DNA damage, it appears that SMRT is necessary for DNA repairs during AT<jats:sub>1<\/jats:sub>R-BLK. We conclude that AT<jats:sub>1<\/jats:sub>R-BLK provides podocyte protection in adverse milieus predominantly through SMRT expression and partly through unliganded VDR expression in 1,25(OH)<jats:sub>2<\/jats:sub>D-deficient states; on the other hand, AT<jats:sub>1<\/jats:sub>R-BLK contributes to liganded VDR expression in 1,25(OH)<jats:sub>2<\/jats:sub>D-sufficient states.<\/jats:p>","DOI":"10.1152\/ajprenal.00476.2014","type":"journal-article","created":{"date-parts":[[2015,6,18]],"date-time":"2015-06-18T01:21:43Z","timestamp":1434590503000},"page":"F189-F203","source":"Crossref","is-referenced-by-count":6,"title":["AT<sub>1<\/sub>R blockade in adverse milieus: role of SMRT and corepressor complexes"],"prefix":"10.1152","volume":"309","author":[{"given":"Tejinder","family":"Singh","sequence":"first","affiliation":[{"name":"Department of Medicine, Hofstra North Shore-LIJ Medical School and Feinstein Institute for Medical Research, Hempstead, New 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