Connective tissue growth factor mediates the profibrotic effects of transforming growth factor-beta produced by tubular epithelial cells in response to high glucose

It was reported that connective tissue growth factor (CTGF) was expressed in the tubular epithelial cells of the diabetic kidney. CTGF has, among other factors, been implicated in mediating the downstream, profibrotic effects of transforming growth factor-beta (TGF-beta), though is precise role in interstitial fibrogenesis in the diabetic kidney has not yet been clarified. We employed a coculture system involving cultured murine proximal tubular epithelial cells (mProx24) and renal fibroblasts (TFB), as a model of the subepithelial mesenchyme in the kidney in order to examine the profibrotic effects of CTGF derived from mProx24 cells in response to high glucose (30 mM). We showed that glucose stimulated CTGF expression in cultured mProx24 in both a dose- and a time-dependent manner, and that this effect was mediated by increased levels of TGF-beta. We also found that high glucose significantly stimulated TFB cells to produce profibrotic molecules, such as type I collagen, the EIIIA isoform of fibronectin, and plasminogen activator inhibitor-1. The induction of these molecules was both direct and indirect, the latter induction being mediated by mProx24 cell-derived CTGF, which, in turn, was induced by TGF-beta that was produced by the mProx24 cells. CTGF plays an important role in mediating renal interstitial fibrogenesis in response to high glucose and, as such, is a reasonable target for anti-fibrotic therapy.