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Curcumin blocks multiple sites of the TGF-beta signaling cascade in renal cells
Jens Gaedeke1, Nancy A Noble, Wayne A Border
1Fibrosis Research Laboratory, Division of Nephrology, University of Utah, Salt Lake City, Utah, USA.
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.
Insights
Curcumin, an AP-1 inhibitor, effectively reduces transforming growth factor-beta (TGF-beta) profibrotic actions in kidney fibroblasts by down-regulating TGF-beta receptors and inhibiting c-jun activity. These findings suggest curcumin
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Overexpression of transforming growth factor-beta (TGF-beta) is a key driver of fibrotic kidney disease.
- Curcumin, a natural compound, has demonstrated antifibrotic effects in other models.
- This study explores curcumin's impact on TGF-beta signaling in renal cells.
Purpose of the Study:
- To investigate curcumin's ability to inhibit TGF-beta-induced profibrotic responses in vitro.
- To elucidate the molecular mechanisms by which curcumin modulates TGF-beta signaling.
Main Methods:
- NRK49F rat renal fibroblasts were treated with TGF-beta and curcumin.
- Gene and protein expression, TGF-beta receptors, and SMAD phosphorylation were analyzed.
- RNA interference (RNAi) was used to deplete c-jun levels.
Main Results:
- Curcumin dose-dependently reduced TGF-beta-induced expression of PAI-1, fibronectin, and collagen I.
- Prolonged curcumin treatment decreased TGF-beta receptor type II levels and SMAD2/3 phosphorylation.
- C-jun depletion mimicked some, but not all, of curcumin's effects.
Conclusions:
- Curcumin inhibits TGF-beta's profibrotic actions in renal fibroblasts.
- Mechanisms include down-regulation of TGF-beta receptor type II and partial inhibition of c-jun.
- Curcumin shows potential as an antifibrotic therapeutic for chronic kidney disease.
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