Connective Tissue Growth Factor-(CTGF, CCN2) – A Marker, Mediator and Therapeutic Target for Renal Fibrosis

Abstract

Connective tissue growth factor (CTGF, CCN2) is a key mediator of tissue fibrosis. CCN2 plays an important role in the development of glomerular and tubulointerstitial fibrosis in progressive kidney diseases. In this review, we discuss the biology of CCN2 with a focus on the regulation of CCN2 gene, cellular mechanisms of profibrotic CCN2 effects and the current in vivo and in vitro evidence for the role of CCN2 in the development of renal fibrosis. We also discuss the therapeutic potential of targeting CCN2 for the treatment of renal fibrosis.

The C-terminal module IV of connective tissue growth factor is a novel immune modulator of the Th17 response

“…16 CCN2 is known to function downstream of TGF-b, driving extracellular matrix accumulation and fibrosis. 2,12 Indeed, in cultured renal cells, CCN2 blockade diminished matrix proteins synthesis induced by TGF-b and Angiotensin II. 59 Although initial studies in fibroblasts, and other cultured cells, showed that recombinant CCN2, both the C-terminal and the full molecule, induce extracellular matrix production, 2,7,14 several in vivo studies have shown that CCN2 alone is not sufficient to cause ongoing fibrotic changes.…”

“…CCN2 overexpression has been described in human fibrotic diseases, and it is produced temporally and spatially in close proximity to fibrotic areas. 2,12 Antagonists of CCN2 have proven effective in blocking profibrogenic CCN2 signaling pathways in vitro and have yielded promising data with respect to preventing experimental fibrosis. 14 Regarding renal diseases, knockdown of CCN2 gene expression with antisense gene transfer into rat kidney ameliorates tubulointerstitial fibrosis in obstructive nephropathy 14 and in experimental mice diabetes in C57BL/6 mice.…”

“…11 CCN2 has been found overexpressed in almost all human disorders characterized by excessive scarring and fibrosis. 2,12 The concept of CCN2 as a downstream mediator of profibrotic factors, including transforming growth factor-b (TGF-b) and Angiotensin II, is the chief operating paradigm in the field. 13,14 Therapeutic approaches that selectively block endogenous CCN2 activity have proven beneficial effects in fibrotic-related diseases, including experimental lung, liver, vascular, and renal diseases, and some authors have suggested that CCN2 could be a therapeutic target for fibrosis.…”

Pathophysiological Mechanisms of Renal Fibrosis: A Review of Animal Models and Therapeutic Strategies

“…On the other hand, induction of CTGF by TGFβ1 is markedly inhibited by SMAD7 overexpression (30,36). In another study, in vivo results showed that Ang II directly activates the SMAD pathway in the vessel wall and regulates numerous SMAD-dependent proteins implicated in vascular fibrosis, by a direct TGFβ independent mechanism (37).…”

Yin and Yang revisited: CCN3 as an anti-fibrotic therapeutic?

“…Indeed, CCN2 is a wellestablished downstrem mediator of fibrosis (Abdel Wahab and Mason 2004;Phanish et al 2010;Fragiadaki et al 2012;Liu et al 2013). However, issues of possible functional redundancy among CCN family members exist; for example, both CCN4 and CCN6 have been proposed to be potent fibrogenic mediators (Königshoff et al 2009;Jian et al 2014;Batmunkh et al 2011).…”