Vitamin D receptor deficit induces activation of renin angiotensin system via SIRT1 modulation in podocytes.
Vitamin D receptor deficit induces activation of renin angiotensin system via SIRT1 modulation in podocytes.
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DOI：
10.1016/j.yexmp.2017.01.001
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发表时间：
2017-02
影响因子：
3.6
通讯作者：
Singhal PC
中科院分区：
文献类型：
--
作者：
Chandel N;Ayasolla K;Wen H;Lan X;Haque S;Saleem MA;Malhotra A;Singhal PC
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。我们假设缺乏VDR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）和血管紧张素原II型1受体（AT1R）的转录，导致RAS的激活。VDR突变体(M)小鼠的肾脏组织显示p53、Agt、肾素和AT1R的表达增加。体外研究发现，敲除VDR的足细胞不仅上调p53，还增强了Agt、肾素和AT1R的表达。VDR缺陷足细胞也显示p53、Agt、肾素和AT1R的mRNA表达增加。有趣的是，VDR- m和VDR杂合(h)小鼠的肾脏组织显示去乙酰化酶SIRT1的表达减弱。VDR-M小鼠肾组织显示p53赖氨酸(K) 382残基乙酰化，推断肾组织中p53表达增强可能是持续乙酰化的结果，这是SIRT1缺陷状态的结果。值得注意的是，缺乏SIRT1的足细胞不仅在赖氨酸(K) 382残基上显示p53乙酰化，而且p53表达增强。SIRT1/VDR沉默或高糖治疗均可增强足细胞PPAR-y的表达，而其裂解物与抗类视黄醇X受体（RXR）抗体的免疫沉淀（IP）显示PPAR-y的存在。似乎SIRT1的缺失导致了PPAR-y的表达降低，或者足细胞中PPAR-y的表达增强（在没有VDR的情况下）导致了SIRT1的下调。
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.