Chandel Nirupama, Ayasolla Kamesh, Wen Hongxiu, Lan Xiqian, Haque Shabirul, Saleem Moin A, Malhotra Ashwani, Singhal Pravin C
Department of Medicine, Hofstra Northwell Health Medical School and Feinstein Institute for Medical Research, New York, USA.
Renal Academic Unit, University of Bristol, UK.
Exp Mol Pathol. 2017 Feb;102(1):97-105. doi: 10.1016/j.yexmp.2017.01.001. Epub 2017 Jan 6.
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.
维生素D受体（VDR）缺乏状态已被证明与肾素血管紧张素系统（RAS）的激活有关。我们假设VDR的缺乏会通过下调SIRT1来增强足细胞中p53的表达；前者会增强血管紧张素原（Agt）和血管紧张素II 1型受体（AT1R）的转录，从而导致RAS的激活。VDR突变（M）小鼠的肾组织中p53、Agt、肾素和AT1R的表达增加。在体外研究中，VDR基因敲除的足细胞不仅p53表达上调，而且Agt、肾素和AT1R的表达也增强。VDR缺乏的足细胞中p53、Agt、肾素和AT1R的mRNA表达也增加。有趣的是，VDR-M小鼠以及VDR杂合（h）小鼠的肾组织中去乙酰化酶SIRT1的表达减弱。VDR-M小鼠的肾组织显示p53在赖氨酸（K）382残基处发生乙酰化，这表明肾组织中p53表达增强可能是持续乙酰化的结果，是SIRT1缺乏状态的一个后果。值得注意的是，缺乏SIRT1的足细胞不仅显示p53在赖氨酸（K）382残基处发生乙酰化，而且p53表达也增强。沉默SIRT1/VDR或用高糖处理均可增强足细胞PPAR-γ的表达，而用抗维甲酸X受体（RXR）抗体对其裂解物进行免疫沉淀（IP）显示存在PPAR-γ。似乎要么是SIRT1的缺乏解除了对PPAR-γ表达的抑制，要么是（在没有VDR的情况下）足细胞中PPAR-γ表达的增强导致了SIRT1的下调。
