title: AT1R blockade in adverse milieus: role of SMRT and corepressor complexes.
abstract: ANG II type 1 receptor blockade (AT1R-BLK) is used extensively to slow down the progression of proteinuric kidney diseases. We hypothesized that AT1R-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 AT1R-BLK and VDR agonists (VDAs) stimulated VDR complex formation that differed not only in their composition but also in their functionality. AT1R-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. AT1R-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. AT1R-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 AT1R-BLK-mediated protection against DNA damage, it appears that SMRT is necessary for DNA repairs during AT1R-BLK. We conclude that AT1R-BLK provides podocyte protection in adverse milieus predominantly through SMRT expression and partly through unliganded VDR expression in 1,25(OH)2D-deficient states; on the other hand, AT1R-BLK contributes to liganded VDR expression in 1,25(OH)2D-sufficient states.
authors.affiliation: Department of Medicine, Hofstra North Shore-LIJ Medical School and Feinstein Institute for Medical Research, Hempstead, New York;
authors.forename: Tejinder
authors.initials: T
authors.lastname: Singh
authors.affiliation: Department of Medicine, Hofstra North Shore-LIJ Medical School and Feinstein Institute for Medical Research, Hempstead, New York;
authors.forename: Kamesh
authors.initials: K
authors.lastname: Ayasolla
authors.affiliation: Department of Medicine, Hofstra North Shore-LIJ Medical School and Feinstein Institute for Medical Research, Hempstead, New York;
authors.forename: Partab
authors.initials: P
authors.lastname: Rai
authors.affiliation: Department of Medicine, Hofstra North Shore-LIJ Medical School and Feinstein Institute for Medical Research, Hempstead, New York;
authors.forename: Nirupama
authors.initials: N
authors.lastname: Chandel
authors.affiliation: Department of Medicine, Hofstra North Shore-LIJ Medical School and Feinstein Institute for Medical Research, Hempstead, New York;
authors.forename: Shabirul
authors.initials: S
authors.lastname: Haque
authors.affiliation: Department of Medicine, Hofstra North Shore-LIJ Medical School and Feinstein Institute for Medical Research, Hempstead, New York;
authors.forename: Rivka
authors.initials: R
authors.lastname: Lederman
authors.affiliation: Jamia Millia Islamia, New Delhi, India.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Husain
authors.affiliation: Department of Medicine, Hofstra North Shore-LIJ Medical School and Feinstein Institute for Medical Research, Hempstead, New York;
authors.forename: Vasupradha
authors.initials: V
authors.lastname: Vethantham
authors.affiliation: Department of Medicine, Hofstra North Shore-LIJ Medical School and Feinstein Institute for Medical Research, Hempstead, New York;
authors.forename: Amrita
authors.initials: A
authors.lastname: Chawla
authors.affiliation: Nephrology Division, Ochsner Health System, New Orleans, Louisiana;
authors.forename: Himanshu
authors.initials: H
authors.lastname: Vashistha
authors.affiliation: Academic Renal Unit, University of Bristol, Bristol, United Kingdom;
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.affiliation: Nephrology Division, Renmin Hospital of Wuhan, Wuhan, China, and.
authors.forename: Guohua
authors.initials: G
authors.lastname: Ding
authors.affiliation: Department of Pathology, New York Medical College, Valhalla, New York.
authors.forename: Praveen N
authors.initials: PN
authors.lastname: Chander
authors.affiliation: Department of Medicine, Hofstra North Shore-LIJ Medical School and Feinstein Institute for Medical Research, Hempstead, New York;
authors.forename: Ashwani
authors.initials: A
authors.lastname: Malhotra
authors.affiliation: Nephrology Division, Ochsner Health System, New Orleans, Louisiana;
authors.forename: Leonard G
authors.initials: LG
authors.lastname: Meggs
authors.affiliation: Department of Medicine, Hofstra North Shore-LIJ Medical School and Feinstein Institute for Medical Research, Hempstead, New York; psinghal@nshs.edu.
authors.forename: Pravin C
authors.initials: PC
authors.lastname: Singhal
mesh_terms: D000107:Acetylation; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D056970:Co-Repressor Proteins / Q000187:drug effects; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D006657:Histones / Q000378:metabolism; D006801:Humans; D019808:Losartan / Q000494:pharmacology; D056985:Nuclear Receptor Co-Repressor 2 / Q000502:physiology*; D050199:Podocytes / Q000187:drug effects / Q000201:enzymology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology; D018167:Receptors, Calcitriol / Q000187:drug effects; D065668:Vitamin D3 24-Hydroxylase / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D051017:Apoptosis Regulatory Proteins; D056970:Co-Repressor Proteins; D006657:Histones; C539130:NCOR2 protein, human; D056985:Nuclear Receptor Co-Repressor 2; D020011:Protective Agents; D018167:Receptors, Calcitriol; D065668:Vitamin D3 24-Hydroxylase; D046988:Proteasome Endopeptidase Complex; D019808:Losartan
keywords: angiotensin II; angiotensin II type 1 receptor blockade; glucose; silencing mediator of retinoic acid and thyroid hormone receptor; vitamin D receptor