Imbalance of growth factor signalling in diabetic kidney disease: is connective tissue growth factor (CTGF, CCN2) the perfect intervention point?

Abstract

The prevalence of diabetes mellitus and its clinical complications are increasing rapidly worldwide. Diabetic nephropathy has already become the leading cause of end-stage renal disease in developed countries and is thus forming an increasing clinical problem [1]. Mesangial matrix accumulation and glomerular basement membrane (GBM) thickening are primary structural alterations characteristic for diabetic nephropathy [2]. These structural changes are accompanied by increased permeability of the GBM for proteins, resulting in increased urinary albumin excretion (UAE). Growth factors and cytokines such as transforming growth factor-b (TGF-b), growth hormone, insulin-like growth factor (IGF) and vascular endothelial growth factor (VEGF) play important roles in the development of diabetic nephropathy [2,3]. In addition to these ‘pro-fibrotic’ growth factors, the ‘anti-fibrotic’ growth factor bone morphogenetic protein-7 (BMP-7) has been reported to be downregulated in diabetic nephropathy, and addition of BMP-7 in experimental diabetes is capable of antagonizing renal fibrosis [4]. TGF-b is generally accepted to be the main pro-fibrotic factor in diabetic nephropathy. Several studies have reported that TGF-b is upregulated in diabetes and induces matrix accumulation in vitro and in vivo. Inhibition of TGF-b by administration of neutralizing antibodies or antisense oligonucleotides, or by blocking its downstream signalling pathway all result in prevention of the fibrotic process in diabetic nephropathy [1]. However, since TGF-b also has important anti-proliferative and anti-inflammatory effects, inhibition of TGF-b may be a double-edged sword. Therefore, alternative targets for therapeutic intervention are needed to treat this complication of diabetes mellitus. A few years ago, connective tissue growth factor (CTGF) was proposed as a potential target for anti-fibrotic strategies. The question was asked whether CTGF is just another factor in renal fibrosis, or a particularly interesting key player in tissue response to injury [5]. As will become apparent from this review, recent evidence does indeed support a prominent role for CTGF in the pathogenesis of diabetic nephropathy, both as a downstream effector of profibrotic TGF-b action and as an extracellular mediator of cross-talk between various growth factor signalling pathways implicated in diabetic kidney disease.