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: Tejinder Singh, Kamesh Ayasolla, Partab Rai, Nirupama Chandel, Shabirul Haque, Rivka Lederman, Mohammad Husain, Vasupradha Vethantham, Amrita Chawla, Himanshu Vashistha, Moin A Saleem, Guohua Ding, Praveen N Chander, Ashwani Malhotra, Leonard G Meggs, Pravin C Singhal
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 309 Issue 3 Pg. F189-203 (Aug 01 2015) ISSN: 1522-1466 [Electronic] United States
• PMID: 26084932 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 the American Physiological Society.

Chemical References

• Angiotensin II Type 1 Receptor Blockers
• Apoptosis Regulatory Proteins
• Co-Repressor Proteins
• Histones
• NCOR2 protein, human
• Nuclear Receptor Co-Repressor 2
• Protective Agents
• Receptors, Calcitriol
• Vitamin D3 24-Hydroxylase
• Proteasome Endopeptidase Complex
• Losartan

Topics

• Acetylation
• Angiotensin II Type 1 Receptor Blockers (pharmacology)
• Apoptosis Regulatory Proteins (biosynthesis)
• Co-Repressor Proteins (drug effects)
• DNA Damage
• Dose-Response Relationship, Drug
• Histones (metabolism)
• Humans
• Losartan (pharmacology)
• Nuclear Receptor Co-Repressor 2 (physiology)
• Podocytes (drug effects, enzymology)
• Proteasome Endopeptidase Complex (drug effects)
• Protective Agents (pharmacology)
• Receptors, Calcitriol (drug effects)
• Vitamin D3 24-Hydroxylase (biosynthesis, metabolism)