Connective tissue growth factor antagonizes transforming growth factor-?1/Smad signalling in renal mesangial cells

Abstract

The critical involvement of TGF-?1 (transforming growth factor-?1) in DN (diabetic nephropathy) is well established. However, the role of CTGF (connective tissue growth factor) in regulating the complex interplay of TGF-?1 signalling networks is poorly understood. The purpose of the present study was to investigate co-operative signalling between CTGF and TGF-?1 and its physiological significance. CTGF was determined to bind directly to the T?RIII (TGF-? type III receptor) and antagonize TGF-?1-induced Smad phosphorylation and transcriptional responses via its N-terminal half. Furthermore, TGF-?1 binding to its receptor was inhibited by CTGF. A consequent shift towards non-canonical TGF-?1 signalling and expression of a unique profile of differentially regulated genes was observed in CTGF/TGF-?1-treated mesangial cells. Decreased levels of Smad2/3 phosphorylation were evident in STZ (streptozotocin)-induced diabetic mice, concomitant with increased levels of CTGF. Knockdown of T?RIII restored TGF-?1-mediated Smad signalling and cell contractility, suggesting that T?RIII is key for CTGFmediated regulation of TGF-?1. Comparison of gene expression profiles from CTGF/TGF-?1-treated mesangial cells and human renal biopsy material with histological diagnosis of DN revealed significant correlation among gene clusters. In summary, mesangial cell responses to TGF-?1 are regulated by cross-talk with CTGF, emphasizing the potential utility of targeting CTGF in DN.