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      1, 25-dihydroxyvitamin D3 decreases adriamycin-induced podocyte apoptosis and loss

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          Abstract

          Background: Selective proteinuria is frequently observed in glomerular diseases characterized by podocyte injury. Although, 1,25-dihydroxyvitamin D3 [1,25(OH) 2D 3] has potential therapeutic effects on chronic kidney diseases through decreasing podocyte loss, the mechanism underlying the beneficial effects of 1,25(OH) 2D 3 on podocytes remains still unknown. The present study tested the hypothesis that 1,25(OH) 2D 3 directly reduced podocyte apoptosis and loss.

          Methods: Sprague-Dawley (SD) rats were randomly assigned into three groups: Adriamycin (ADR) group (n=15), ADR+1,25-(OH) 2D 3 group (n=16), and control group (n=16). Rats in ADR+1,25-(OH) 2D 3 group were treated with 1,25(OH) 2D 3 for 8 weeks. The number of podocytes and foot process width (FPW) were detected by transmission electron microscopy. The number of apoptotic podocytes per glomerulus and that of apoptotic nuclei and caspase-3 activity in cultured podocytes were determined by TUNEL staining. The average number of podocytes per glomerulus was quantified by immunohistochemistry. Expressions of p-Smad2/3, p-Smad1/5/8, Fas, Fas-Associated protein with Death Domain (FADD), Bax, and Bcl-2 proteins were examined by Western blot assay.

          Results: Compared with control group, proteinuria, FPW, apoptotic podocytes, caspase-3 activity, the protein expressions of p-Smad2/3, Fas, FADD, and Bax were significantly increased, podocyte density, p-Smad1/5/8 and Bcl-2 expression were decreased in ADR group. 1,25(OH) 2D 3 significantly reduced proteinuria, FPW, caspase-3 activity, expressions of p-Smad2/3, Fas, FADD, and Bax and apoptosis of podocytes, but increased serum albumin, number of viable podocytes , p-Smad1/5/8 and Bcl-2 expression in ADR treated rats.

          Conclusion: ADR-induced podocyte apoptosis was associated with the imbalance of p-Smad2/3, p-Smad1/5/8 the activity of caspase-3 and aberrant expressions of, Fas, FADD, Bax and Bcl-2. The beneficial effects of 1,25(OH) 2D 3 on podocytes may be attributable to inhibit podocyte apoptosis and the amelioration of podocytopenia.

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          1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system.

          Yan Li, Juan Kong, Minjie Wei … (2002)
          Inappropriate activation of the renin-angiotensin system, which plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis, may represent a major risk factor for hypertension, heart attack, and stroke. Mounting evidence from clinical studies has demonstrated an inverse relationship between circulating vitamin D levels and the blood pressure and/or plasma renin activity, but the mechanism is not understood. We show here that renin expression and plasma angiotensin II production were increased severalfold in vitamin D receptor-null (VDR-null) mice, leading to hypertension, cardiac hypertrophy, and increased water intake. However, the salt- and volume-sensing mechanisms that control renin synthesis are still intact in the mutant mice. In wild-type mice, inhibition of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] synthesis also led to an increase in renin expression, whereas 1,25(OH)(2)D(3) injection led to renin suppression. We found that vitamin D regulation of renin expression was independent of calcium metabolism and that 1,25(OH)(2)D(3) markedly suppressed renin transcription by a VDR-mediated mechanism in cell cultures. Hence, 1,25(OH)(2)D(3) is a novel negative endocrine regulator of the renin-angiotensin system. Its apparent critical role in electrolytes, volume, and blood pressure homeostasis suggests that vitamin D analogues could help prevent or ameliorate hypertension.
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            1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells.

            A. Boonstra, F. J. Barrat, C Crain … (2001)
            1alpha,25-Dihydroxyvitamin D3 (vitD3) is an immunoregulatory hormone with beneficial effects on Th1 mediated autoimmune diseases. Although the inhibitory effects of vitD3 on macrophages and dendritic cells are well documented, any direct effects of vitD3 on Th cell development are not clearly defined. Using CD4(+)Mel14(+) T cells derived from mice on a BALB/c and a C57BL/6 genetic background we examined the effect of vitD3 on Th cell development. We demonstrated that vitD3 affects Th cell polarization by inhibiting Th1 (IFN-gamma production) and augmenting Th2 cell development (IL-4, IL-5, and IL-10 production). These effects were observed in cultures driven with splenic APC and Ag, as well as with anti-CD3 and anti-CD28 alone, indicating that CD4(+) cells can also be direct targets for vitD3. The enhanced Th2 development by vitD3 was found in both BALB/c and C57BL/6 mice. An increased expression of the Th2-specific transcription factors GATA-3 and c-maf correlated with the increased production of Th2 cytokines after vitD3 treatment. The vitD3-induced effects were largely mediated via IL-4, because neutralization of IL-4 almost completely abrogated the augmented Th2 cell development after vitD3 treatment. These findings suggest that vitD3 acts directly on Th cells and can, in the absence of APC, enhance the development of a Th2 phenotype and augment the expression of the transcription factors c-maf and GATA-3. Our findings suggest that the beneficial effects of vitD3 in autoimmune diseases and transplantation operate through prevention of strong Th1 responses via the action on the APC, while simultaneously directly acting on the T cell to enhance Th2 cell development.
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              Podocyte biology and response to injury.

              Stuart Shankland, Peter Mundel (2002)
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Med Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Medical Sciences
                Publisher: Ivyspring International Publisher (Sydney )
                ISSN (Electronic): 1449-1907
                Publication date Collection: 2010
                Publication date (Electronic): 24 August 2010
                Volume: 7
                Issue: 5
                Pages: 290-299
                Affiliations
                1. Department of Pediatrics, Wuhan General Hospital of Guangzhou Command, Wuhan 430070, China
                2. Department of Nephrology, Affiliated Children Hospital of Shanghai Jiaotong University, Shanghai, China
                Author notes
                ✉ Corresponding author: Jian Yu, Department of Pediatrics, Wuhan General Hospital of Guangzhou Command, Wuhan 430070, China. Email: docjack99@ 123456gmail.com

                Conflict of Interest: The authors have declared that no conflict of interest exists.

                Article
                Publisher ID: ijmsv07p0290
                PMC ID: 2934728
                PubMed ID: 20827429
                SO-VID: 2084d0b0-2ff7-49c1-a2cc-2ceaf8e15413
                Copyright © © Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.
                History
                Date received : 26 May 2010
                Date accepted : 17 August 2010
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Medicine
                Keywords: 1,25-dihydroxyvitamin d3,podocyte,proteinuria
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: 1, 25-dihydroxyvitamin d3, podocyte, proteinuria

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