Curcumin blocks multiple sites of the TGF-beta signaling cascade in renal cells

Kidney Int. 2004 Jul;66(1):112-20. doi: 10.1111/j.1523-1755.2004.00713.x.

Abstract

Background: Over-expression of transforming growth factor-beta (TGF-beta) contributes greatly to fibrotic kidney disease. The activator protein-1 (AP-1) inhibitor curcumin, a polyphenolic compound derived from Curcuma longa, has been shown to reduce collagen accumulation in experimental pulmonary fibrosis. Here, we investigate curcumin's ability to modulate TGF-beta's profibrotic actions in vitro.

Methods: NRK49F rat renal fibroblasts were stimulated with TGF-beta (5 ng/mL), and the effects of curcumin on TGF-beta-regulated genes, TGF-beta receptors, and phosphorylated SMAD isoforms were analyzed by Northern blotting, enzyme-linked immunosorbent assay (ELISA), and Western blotting. The effects of c-jun depletion on TGF-beta-regulated gene and protein expression were analyzed with RNAi.

Results: When applied 30 minutes before TGF-beta, curcumin dose dependently and dramatically reduced TGF-beta-induced increases in plasminogen activator inhibitor-1 (PAI-1), TGF-beta1, fibronectin (FN) and collagen I (Col I) mRNA, and in PAI-1 and fibronectin protein. Prolonged curcumin treatment (>6 h) significantly reduced TGF-beta receptor type II levels and SMAD2/3 phosphorylation in response to added TGF-beta. Depletion of cellular c-jun levels with a RNAi method mimicked the effects of curcumin on expression of TGF-beta1, FN, and Col I, but not PAI-1.

Conclusion: Curcumin blocks TGF-beta's profibrotic actions on renal fibroblasts through down-regulation of TbetaRII, and through partial inhibition of c-jun activity. These in vitro data suggest that curcumin might be an effective antifibrotic drug in the treatment of chronic kidney disease.

MeSH terms

  • Animals
  • Cells, Cultured
  • Curcumin / administration & dosage
  • Curcumin / pharmacology*
  • DNA-Binding Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Fibroblasts / metabolism
  • Fibronectins / metabolism
  • Fibrosis
  • Gene Expression / drug effects
  • Glomerular Mesangium / drug effects
  • Kidney / metabolism*
  • Kidney / pathology
  • Phosphorylation / drug effects
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-jun / metabolism
  • Rats
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors
  • Signal Transduction / drug effects*
  • Smad2 Protein
  • Smad3 Protein
  • Time Factors
  • Trans-Activators / metabolism
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta / pharmacology

Substances

  • DNA-Binding Proteins
  • Fibronectins
  • Plasminogen Activator Inhibitor 1
  • Proto-Oncogene Proteins c-jun
  • Receptors, Transforming Growth Factor beta
  • Smad2 Protein
  • Smad2 protein, rat
  • Smad3 Protein
  • Smad3 protein, rat
  • Trans-Activators
  • Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • Curcumin