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.

Vitamin D and Cardiovascular Risk: Which Implications in Children?

“…In animal experiments, vitamin D was found to be a potent endocrine suppressor of renin biosynthesis: VDR -/mice had elevated production of renin and angiotensin II, causing hypertension, cardiac hypertrophy, and increased water intake [24,25]. Chandel et al [26] analyzed how VDR modulates the RAAS activity finding that vitamin D receptor deficit induces its activation through SIRT1/PPAR-c/VDR signaling in podocytes. Zittermann et al [27] evaluated the effect of three years of vitamin D supplementation (4000 IU daily) on parameters of the RAAS (renin and aldosterone) in 165 patients with advanced heart failure, with a not significant change in RAAS parameters; nevertheless, the study showed an increase in serum renin concentrations in the subgroup with low baseline 25OHD levels.…”

Vitamin D Receptor: A Novel Therapeutic Target for Kidney Diseases

“…Vitamin D deficiency aggravates tenofovir-induced nephrotoxicity because of enhanced activation of the RAS in the kidney [ 91 ]. In vitro studies confirm that VDR knockout podocytes display upregulation of angiotensinogen [ 92 ]. In rats with diabetes, calcitriol treatment attenuates renal pathological abnormalities by blocking the activation of the local RAS [ 93 - 95 ].…”

Charting the transcriptional landscape of cells of renin lineage following podocyte depletion

“…al . recently demonstrated that Pparg expression is downregulated in podocytes from vitamin D receptor ( Vdr ) null mice via a mechanism involving suppression of sirtuin 1 ( Sirt1 ) [ 51 ]. While we did not observe downregulation of Sirt1 in our model, Vdr was significantly suppressed in CoRL at day 5 post-FSGS induction (FDR < 0.01).…”