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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.

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