At(1)R Blockade In Adverse Milieus: Role Of Smrt And Corepressor Complexes

ANG II type 1 receptor blockade (AT(1)R-BLK) is used extensively to slow down the progression of proteinuric kidney diseases. We hypothesized that AT(1)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(1)R-BLK and VDR agonists (VDAs) stimulated VDR complex formation that differed not only in their composition but also in their functionality. AT(1)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(1)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(1)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(1)R-BLK-mediated protection against DNA damage, it appears that SMRT is necessary for DNA repairs during AT(1)R-BLK. We conclude that AT(1)R-BLK provides podocyte protection in adverse milieus predominantly through SMRT expression and partly through unliganded VDR expression in 1,25(OH)(2)D-deficient states; on the other hand, AT(1)R-BLK contributes to liganded VDR expression in 1,25(OH)(2)D-sufficient states.