Downregulation of Smad transcriptional corepressors SnoN and Ski in the fibrotic kidney: an amplification mechanism for TGF-beta1 signaling.
|
| Abstract |
TGF-beta1 is a profibrotic cytokine that plays a central role in the onset and progression of chronic renal diseases. The activity of TGF-beta1 is tightly controlled by multiple mechanisms, in which antagonizing Smad-mediated gene transcription by co-repressors is an important regulatory component. This study examined the expression of Smad transcriptional co-repressors in the fibrotic kidney and investigated their potential functions in controlling TGF-beta1 response. Western blot analysis demonstrated that the protein levels of Smad transcriptional co-repressors SnoN and Ski were progressively reduced in a time-dependent manner in the fibrotic kidney induced by unilateral ureteral obstruction in mice, whereas renal Smad abundance was relatively unaltered. Consistently, SnoN and Ski staining was diminished in the nuclei of renal tubular epithelium and interstitium after obstructive injury. In vitro, knockdown of SnoN expression by RNA interference in tubular epithelial cells dramatically sensitized their responsiveness to TGF-beta1 stimulation. Conversely, ectopic expression of exogenous SnoN or Ski after transfection conferred tubular epithelial cell resistance to TGF-beta1-induced epithelial to myofibroblast transition. Both SnoN and Ski could block Smad-mediated activation of TGF-beta1-responsive promoter and exhibited additive effect in abrogating the profibrotic actions of TGF-beta1. These results indicate that as a result of loss of Smad transcriptional co-repressors, the profibrotic TGF-beta1 signaling in diseased kidney is markedly amplified in a magnitude much greater than previously thought. Therefore, new strategy aimed to increase Smad transcriptional co-repressors expression may be effective in antagonizing TGF-beta1 signaling and thereby blocking the progression of chronic renal fibrosis.
|
|---|---|
| Authors | Junwei Yang, Xianghong Zhang, Yingjian Li, Youhua Liu |
| Journal | Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 14 Issue 12 Pg. 3167-77 (Dec 2003) ISSN: 1046-6673 [Print] United States |
| PMID | 14638915 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.) |
| Chemical References |
|
| Topics |
|
Join CureHunter, for free Research Interface BASIC access!
Realize the full power of the drug-disease research graph!