CCN3 (NOV): A Negative Regulator of CCN2 (CTGF) Activity and an Endogenous Inhibitor of Fibrosis in Experimental Diabetic Nephropathy

The fibrosis that occurs in the kidney is a common complication of diabetes, and a major cause of end stage renal disease (ESRD). Our laboratory has been active in identifying factors responsible for its initiation. However, a lack of understanding of the downstream regulatory pathways has prevented development of specific anti-fibrotic therapies. CCN2 (CTGF) has emerged as a critical molecule acting downstream of TGF-β to drive fibrosis, making it an exciting new therapeutic target. However, suppression of CCN2 has been difficult. In this study, we examined the possibility that CCN3 (NOV), might act as an endogenous negative regulator of CCN2 with the capacity to limit the overproduction of extracellular matrix (ECM), and thus prevent, or ameliorate fibrosis. We demonstrate, using an in vitro model of diabetic renal fibrosis, that both exogenous treatment and transfection with the over-expression of the CCN3 gene in mesangial cells markedly down-regulates CCN2 activity and blocks ECM over-accumulation stimulated by TGF-β. Conversely, TGF-β treatment reduces endogenous CCN3 expression and increases CCN2 activity and matrix accumulation, indicating an important, novel yin/yang effect. Using the db/db mouse model of diabetes, we confirm the expression of CCN3 in the kidney, with temporal localization that supports these in vitro findings. In summary, the results support our hypothesis that CCN3 has a negative regulatory action on CCN2 and the effects of TGF-β, acting to limit ECM turnover and fibrosis in vivo. The findings suggest opportunities for novel endogenous-based therapy either by the administration, or the upregulation of CCN3.