1,25-(OH(2))D(3) alters the transforming growth factor beta signaling pathway in renal tissue

J Surg Res. 2001 Oct;100(2):171-5. doi: 10.1006/jsre.2001.6221.

Abstract

Background: 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) plays an important role in regulating immune responses, in addition to its effects on bone metabolism. The cytokine transforming growth factor beta (TGF-beta) regulates diverse biological processes, including cellular proliferation and differentiation, immune modulation, and modulation of extracellular matrix deposition. 1,25-(OH)(2)D(3) interacts in vitro with Smad proteins, important regulators of TGF-beta signal transduction. We hypothesized that exogenous 1,25-(OH)(2)D(3) would alter levels of TGF-beta(1) and TGF-beta(1) signaling proteins in renal tissue.

Methods: C57BL6 mice and Lewis rats were placed on diets with or without 1,25-(OH)(2)D(3) for 14 days. Renal lysates were examined for TGF-beta(1), vitamin D receptor (VDR), and Smad3 protein levels using a cell proliferation assay and Western blot analysis. Coimmunoprecipitation was used to determine if any interaction between VDR and Smad3 proteins occurs in vivo. Reverse transcription-polymerase chain reaction (RT-PCR) was used to assess messenger RNA (mRNA) levels for all of these molecules.

Results: Vitamin D supplementation decreased VDR and Smad3 protein levels. Coimmunoprecipitation of VDR and Smad3 revealed a Smad3-VDR interaction in vivo. Vitamin D-treated rats had a significant (P = 0.001) reduction in bioactive renal TGF-beta(1). RT-PCR demonstrated no difference in mRNA expression for either VDR or TGF-beta(1).

Conclusion: Our results suggest that vitamin D has a significant effect in regulating levels of bioactive TGF-beta(1) and appears to affect aspects of the TGF-beta(1) signaling system. These effects, in combination with the immunomodulatory actions of vitamin D, may alter the evolution of chronic rejection in renal transplants.

MeSH terms

  • Animals
  • Blotting, Western
  • Calcitriol / pharmacology*
  • Calcium Channel Agonists / pharmacology*
  • Cell Division / drug effects
  • DNA-Binding Proteins / analysis
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Down-Regulation / drug effects
  • Gene Expression / drug effects
  • Graft Rejection / drug therapy
  • Kidney / drug effects
  • Kidney / metabolism*
  • Kidney Transplantation
  • Mice
  • Mice, Inbred C57BL
  • Mink
  • Precipitin Tests
  • Rats
  • Rats, Inbred Lew
  • Receptors, Calcitriol / analysis
  • Receptors, Calcitriol / genetics
  • Receptors, Calcitriol / metabolism
  • Respiratory Mucosa / cytology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects*
  • Smad3 Protein
  • Trans-Activators / analysis
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Transplantation, Homologous

Substances

  • Calcium Channel Agonists
  • DNA-Binding Proteins
  • Receptors, Calcitriol
  • Smad3 Protein
  • Smad3 protein, mouse
  • Smad3 protein, rat
  • Trans-Activators
  • Transforming Growth Factor beta
  • Calcitriol