| First Author | Li Z | Year | 2011 |
| Journal | J Biol Chem | Volume | 286 |
| Issue | 48 | Pages | 41323-30 |
| PubMed ID | 21990365 | Mgi Jnum | J:183188 |
| Mgi Id | MGI:5317995 | Doi | 10.1074/jbc.M111.259184 |
| Citation | Li Z, et al. (2011) Response gene to complement 32 is essential for fibroblast activation in renal fibrosis. J Biol Chem 286(48):41323-30 |
| abstractText | Response gene to complement 32 (RGC-32) is a downstream target of transforming growth factor-beta (TGF-beta). TGF-beta is known to play a pathogenic role in renal fibrosis. In this study, we investigated RGC-32 function in renal fibrosis following unilateral ureteral obstruction (UUO) in mice, a model of progressive tubulointerstitial fibrosis. RGC-32 is normally expressed only in blood vessels of mouse kidney. However, UUO induces RGC-32 expression in renal interstitial cells at the early stage of kidney injury, suggesting that RGC-32 is involved in interstitial fibroblast activation. Indeed, expression of smooth muscle alpha-actin (alpha-SMA), an indicator of fibroblast activation, is limited to the interstitial cells at the early stage, and became apparent later in both interstitial and tubular cells. RGC-32 knockdown by shRNA significantly inhibits UUO-induced renal structural damage, alpha-SMA expression and collagen deposition, suggesting that RGC-32 is essential for the onset of renal interstitial fibrosis. In vitro studies indicate that RGC-32 mediates TGF-beta-induced fibroblast activation. Mechanistically, RGC-32 interacts with Smad3 and enhances Smad3 binding to the Smad binding element in alpha-SMA promoter as demonstrated by DNA affinity assay. In the chromatin setting, Smad3, but not Smad2, binds to alpha-SMA promoter in fibroblasts. RGC-32 appears to be essential for Smad3 interaction with the promoters of fibroblast activation-related genes in vivo. Functionally, RGC-32 is crucial for Smad3-mediated alpha-SMA promoter activity. Taken together, we identify RGC-32 as a novel fibrogenic factor contributing to the pathogenesis of renal fibrosis through fibroblast activation. |
