title: Vitamin D receptor deficit induces activation of renin angiotensin system via SIRT1 modulation in podocytes.
abstract: Vitamin D receptor (VDR) deficient status has been shown to be associated with the activation of renin angiotensin system (RAS). We hypothesized that lack of VDR would enhance p53 expression in podocytes through down regulation of SIRT1; the former would enhance the transcription of angiotensinogen (Agt) and angiotensinogen II type 1 receptor (AT1R) leading to the activation of RAS. Renal tissues of VDR mutant (M) mice displayed increased expression of p53, Agt, renin, and AT1R. In vitro studies, VDR knockout podocytes not only displayed up regulation p53 but also displayed enhanced expression of Agt, renin and AT1R. VDR deficient podocytes also displayed an increase in mRNA expression for p53, Agt, renin, and AT1R. Interestingly, renal tissues of VDR-M as well as VDR heterozygous (h) mice displayed attenuated expression of deacetylase SIRT1. Renal tissues of VDR-M mice showed acetylation of p53 at lysine (K) 382 residues inferring that enhanced p53 expression in renal tissues could be the result of ongoing acetylation, a consequence of SIRT1 deficient state. Notably, podocytes lacking SIRT1 not only showed acetylation of p53 at lysine (K) 382 residues but also displayed enhanced p53 expression. Either silencing of SIRT1/VDR or treatment with high glucose enhanced podocyte PPAR-y expression, whereas, immunoprecipitation (IP) of their lysates with anti-retinoid X receptor (RXR) antibody revealed presence of PPAR-y. It appears that either the deficit of SIRT1 has de-repressed expression of PPAR-y or enhanced podocyte expression of PPAR-y (in the absence of VDR) has contributed to the down regulation of SIRT1.
authors.affiliation: Department of Medicine, Hofstra Northwell Health Medical School and Feinstein Institute for Medical Research, New York, USA.
authors.forename: Nirupama
authors.initials: N
authors.lastname: Chandel
authors.affiliation: Department of Medicine, Hofstra Northwell Health Medical School and Feinstein Institute for Medical Research, New York, USA.
authors.forename: Kamesh
authors.initials: K
authors.lastname: Ayasolla
authors.affiliation: Department of Medicine, Hofstra Northwell Health Medical School and Feinstein Institute for Medical Research, New York, USA.
authors.forename: Hongxiu
authors.initials: H
authors.lastname: Wen
authors.affiliation: Department of Medicine, Hofstra Northwell Health Medical School and Feinstein Institute for Medical Research, New York, USA.
authors.forename: Xiqian
authors.initials: X
authors.lastname: Lan
authors.affiliation: Department of Medicine, Hofstra Northwell Health Medical School and Feinstein Institute for Medical Research, New York, USA.
authors.forename: Shabirul
authors.initials: S
authors.lastname: Haque
authors.affiliation: Renal Academic Unit, University of Bristol, UK.
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.affiliation: Department of Medicine, Hofstra Northwell Health Medical School and Feinstein Institute for Medical Research, New York, USA.
authors.forename: Ashwani
authors.initials: A
authors.lastname: Malhotra
authors.affiliation: Department of Medicine, Hofstra Northwell Health Medical School and Feinstein Institute for Medical Research, New York, USA. Electronic address: psinghal@nshs.edu.
authors.forename: Pravin C
authors.initials: PC
authors.lastname: Singhal
mesh_terms: D000107:Acetylation; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D008957:Models, Genetic; D050199:Podocytes / Q000166:cytology / Q000378:metabolism*; D034622:RNA Interference; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000172:deficiency / Q000235:genetics*; D012083:Renin / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D044140:Receptor, Angiotensin, Type 1; D018167:Receptors, Calcitriol; D016159:Tumor Suppressor Protein p53; D000808:Angiotensinogen; D012083:Renin; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D008239:Lysine