In vitro evidence for differential involvement of CTGF, TGF beta, and PDGF-BB in mesangial response to injury

Background. Connective tissue growth factor (CTGF) is a profibrotic growth factor, which is upregulated in wound healing and renal fibrosis, including anti-Thy-1.1 nephritis. The kinetics of CTGF mRNA expression in anti-Thy-1 .1 nephritis suggested that CTGF regulation might contribute to glomerular response to injury downstream of transforming growth factor-beta (TGF beta) . In anti-Thy-1.1 nephritis the initial damage is followed by mesangial rep air and limited sclerosis, which involves mesangial cell (MC) activation (x -smooth-muscle actin (alpha SMA) expression), proliferation, migration, and extracellular matrix production. The present in vitro study addresses the possible role of CTGF in these different aspects of mesangial response to i njury, and how CTGF activity might relate to effects of TGF beta and platel et-derived growth factor-BE (PDGF-BE). Methods and Results. Immunostaining and ELISA showed that alpha SMA express ion acid transformation of MC into myofibroblast-like cells was induced by TGF beta, but not affected by PDGF-BB, CTGF, or neutralizing anti-CTGF anti bodies. [H-3]thymidine incorporation and Ki67 staining demonstrated that. u nlike PDGF-BB, neither CTGF nor TGF beta induced the proliferation of MC. I n contrast, both CTGF and TGF beta induced MC migration, as evidenced by ap proximation of wound edges in scrape-wounded, non-proliferating rat MC mono layers. In addition, fibronectin expression was upregulated by both CTGF an d TGF beta, as measured by dot-blot analysis. Anti-CTGF completely blocked the effect of added CTGF. Moreover, anti-CTGF significantly reduced TGF bet a -induced increase in fibronectin. Conclusion. It thus appears that CTGF is specifically involved in a subset of the adaptive changes of MC involved in mesangial repair and sclerosis, w hich makes it an interesting candidate target for future intervention strat egies.