1,25-dihydroxyvitamin D inhibits renal interstitial myofibroblast activation by inducing hepatocyte growth factor expression

Kidney Int. 2005 Oct;68(4):1500-10. doi: 10.1111/j.1523-1755.2005.00562.x.


Background: Vitamin D and its metabolites play an important role in calcium homeostasis, bone remodeling, hormone secretion, cell proliferation, and differentiation. Recent studies also suggest a beneficial role of vitamin D in slowing the progression of chronic renal glomerular diseases. This study investigated the effects and potential mechanism of 1,25-dihydroxyvitamin D(3)[1,25(OH)(2)D(3)] on the regulation of myofibroblast activation from interstitial fibroblast, a critical event in generating alpha-smooth muscle actin (alphaSMA)-positive, matrix-producing effector cells in renal interstitial fibrosis.

Methods: Normal rat renal interstitial fibroblast cell line (NRK-49F) was used as a model system. Myofibroblast activation was initiated by incubation with transforming growth factor (TGF)-beta1. Expression of alpha-SMA, collagen I, thrombospondin-1, and hepatocyte growth factor (HGF) was assessed by reverse transcription-polymerase chain reaction (RT-PCR), Western blot, and immunostaining, respectively. HGF promoter activity was evaluated by using luciferase reporter assay.

Results: Incubation of rat renal interstitial fibroblasts (NRK-49F) with 1,25(OH)(2)D(3) suppressed TGF-beta1-induced de novo alpha-SMA expression in a dose-dependent manner. 1,25(OH)(2)D(3) also suppressed type I collagen and thrombospondin-1 expression induced by TGF-beta1. Interestingly, 1,25(OH)(2)D(3) induced HGF mRNA expression and protein secretion in renal interstitial fibroblasts. Transfection studies revealed that 1,25(OH)(2)D(3) stimulated HGF gene promoter activity, which was dependent on the presence of vitamin D response element (VDRE). 1,25(OH)(2)D(3) induced the binding of vitamin D receptor to the VDRE in HGF promoter region. Furthermore, 1,25(OH)(2)D(3) was capable of stimulating HGF receptor phosphorylation in renal fibroblasts. Incubation with specific HGF neutralizing antibody largely abolished 1,25(OH)(2)D(3)-mediated suppression of myofibroblast activation.

Conclusion: These observations suggest that vitamin D analogue possesses renoprotective activity through suppression of the matrix-producing myofibroblast activation. This action of vitamin D is mediated, at least in part, by up-regulating antifibrotic HGF gene expression in renal interstitial fibroblasts.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Calcitriol / pharmacology*
  • Cells, Cultured
  • Collagen Type I / genetics
  • Fibroblasts / cytology
  • Fibroblasts / drug effects*
  • Fibroblasts / physiology
  • Gene Expression / drug effects
  • Hepatocyte Growth Factor / genetics*
  • Hepatocyte Growth Factor / immunology
  • Hepatocyte Growth Factor / metabolism
  • Kidney / cytology*
  • Phosphorylation / drug effects
  • Promoter Regions, Genetic / physiology
  • Proto-Oncogene Proteins c-met / metabolism
  • Rats
  • Thrombospondin 1 / genetics
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta1
  • Up-Regulation / drug effects
  • Vitamins / pharmacology*


  • Antibodies
  • Collagen Type I
  • Tgfb1 protein, rat
  • Thrombospondin 1
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Vitamins
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met
  • Calcitriol