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      1,25–Dihydroxyvitamin D 3 Stimulates Transforming Growth Factor–β1 Synthesis by Mouse Renal Proximal Tubular Cells

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          Abstract

          1,25–Dihydroxyvitamin D<sub>3</sub> [1,25–(OH)<sub>2</sub> D<sub>3</sub>] is a secosteroid hormone with effects on cell growth, differentiation and immunoregulatory functions in a number of tissues not primarily involved in mineral metabolism. We recently demonstrated growth–regulating effects of 1,25–(OH)<sub>2</sub> D<sub>3</sub> on human mesangial cells and proximal tubular cells. To investigate whether 1,25–(OH)<sub>2</sub> D<sub>3</sub> might also affect the synthesis of cytokines and growth factors in proximal tubular cells, we assessed in the present study the expression and secretion of transforming growth factor–β1 (TGF–β1) in a mouse proximal tubular cell line (MCT) in vitro. TGF–β1 synthesis was measured by a monospecific ELISA in culture supernatant. The secreted TGF–β1 was proven to be biologically active by means of a bioassay system (CCL–64 mink lung epithelial cell proliferation assay). TGF–β1 gene expression was assessed by RT–PCR. To analyze whether TGF–β1 expression mediates the 1,25–(OH)<sub>2</sub> D<sub>3</sub>–induced antiproliferative actions in MCT, proliferation studies in the absence or presence of a blocking monoclonal anti TGF–β1–3 antibody were performed. 1,25–(OH)<sub>2</sub> D<sub>3</sub> (10<sup>–11</sup> to 10<sup>–7</sup> M) specifically increased the TGF–β1 protein secretion in MCT with a maximum at 10<sup>–8</sup> M. No detectable effect was found with 25 D<sub>3</sub> at 10 times higher concentrations. A synthetic 20–epi analogue, MC 1288, increased TGF–β1 secretion up to similar amounts at equimolar concentrations as the natural hormone 1,25–(OH)<sub>2</sub> D<sub>3</sub>. Steady–state TGF–β1 mRNA concentration in MCT was transiently increased by 1,25–(OH)<sub>2</sub> D<sub>3</sub> between 12 and 24 h, returning to control values at 48 h. Blocking TGF–β1 did not reduce or abrogate the antiproliferative effect of 1,25–(OH)<sub>2</sub> D<sub>3</sub>. In conclusion, 1,25–(OH)<sub>2</sub> D<sub>3</sub> stimulates TGF–β1 expression in renal proximal tubular cells, a growth factor with anti–inflammatory and profibrotic actions which plays an important role in the development and progression of nephrosclerosis.

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          Suppression of experimental glomerulonephritis by antiserum against transforming growth factor beta 1.

          Glomerulonephritis is an inflammation of the kidney characterized by the accumulation of extracellular matrix within the damaged glomeruli, impaired filtration and proteinuria. In its progressive form, the disease destroys kidney function leading to uraemia and death, unless dialysis therapy or kidney transplantation is available. The pathogenesis of glomerulonephritis is incompletely understood, but the eliciting factor is thought often to be an immunological injury to mesangial and/or other resident cells in the glomeruli. We have used an animal model of acute mesangial proliferative glomerulonephritis to show that this disease is associated with increased production and activity of transforming growth factor beta 1 (TGF-beta 1), an inducer of extracellular matrix production. Here we report that administration of anti-TGF-beta 1 at the time of induction of the glomerular disease suppresses the increased production of extracellular matrix and dramatically attenuates histological manifestations of the disease. These results provide direct evidence for a causal role of TGF-beta 1 in the pathogenesis of the experimental disease and suggest a new approach to the therapy of glomerulonephritis.
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            Immunological properties of vitamin D analogues and metabolites.

             Lise Binderup (1992)
            This commentary has attempted to describe some of the new aspects of our knowledge of the immunological properties of 1 alpha,25(OH)2D3, the physiologically active metabolite of vitamin D3, and its new analogues. These analogues will, in the future, serve as tools to increase our understanding of the role of vitamin D in immunobiology, not only in basal research but also, hopefully, in the therapy of immune-mediated diseases.
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              Author and article information

              Journal
              KBR
              Kidney Blood Press Res
              10.1159/issn.1420-4096
              Kidney and Blood Pressure Research
              S. Karger AG
              1420-4096
              1423-0143
              1999
              1999
              25 June 1999
              : 22
              : 3
              : 99-105
              Affiliations
              Department of Internal Medicine, Division of Nephrology, University Hospital, Zürich, Switzerland
              Article
              25914 Kidney Blood Press Res 1999;22:99–105
              10.1159/000025914
              10394107
              © 1999 S. Karger AG, Basel

              Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

              Page count
              Figures: 4, Tables: 1, References: 32, Pages: 7
              Product
              Self URI (application/pdf): https://www.karger.com/Article/Pdf/25914
              Categories
              Original Paper

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