Diabetic nephropathy (DN) is a common complication of diabetes mellitus (DM) and a major cause of end stage renal disease. DN is a progressive fibrotic kidney disease that is structurally characterized by mesangial matrix accumulation and thickening of the glomerular basement membrane (GBM), and functionally by albuminuria and progressive decrease of the glomerular filtration rate (GFR). Hyperglycemia and hypertension are known risk factors for DN. Both these factors induce the pro-fibrotic growth factor transforming growth factor-β (TGF-β). Experiments in animal models have shown that inhibition of TGF-β can slow down or prevent development of DN. However, as TGF-β is also involved in important anti-inflammatory and anti-proliferative processes, inhibition of TGF-β is not an attractive therapy for DN. Connective tissue growth factor (CTGF) is an important downstream mediator in the fibrotic action of TGF-β. CTGF is upregulated by TGF-Β as well as by the diabetic milieu, which is characterized by hyperglycemia and advanced glycation end products (AGEs), increased levels of reactive oxygen species (ROS), and by mechanical strain (hypertension). The aim of this thesis was to study the role of CTGF in the development of diabetic nephropathy, with a special focus on the potential of CTGF as marker, pathogenic factor, and target for therapeutic intervention of DN. Measurement of CTGF levels in plasma of diabetic patients with and without nephropathy showed that plasma CTGF levels are increased in diabetic patients with DN and that these levels are associated with severity of DN. These data confirm that CTGF might be a useful marker for development and progression of DN. In experimental diabetic mice CTGF was significantly increased in plasma and urine, and urinary CTGF excretion correlated with albuminuria, the main early characteristic of DN. In addition, CTGF mRNA expression was increased in kidney, heart and liver tissue of diabetic mice. We identified the podocyte as the main source of diabetes-induced renal CTGF overexpression. Furthermore, in CTGF heterozygous mice (CTGF+/-), which lack one functional allele of the CTGF gene, we showed that lower CTGF levels in plasma and urine as well as lower CTGF mRNA expression under diabetic conditions, are accompanied by significantly lower albuminuria compared to diabetic CTGF+/+ mice, and by complete absence of GBM-thickening. Thus reduction of CTGF availability in diabetes appears to limit the severity of diabetic nephropathy. Glomerular activity of matrix metalloproteinases (MMPs), which was significantly decreased in diabetic CTGF+/+ mice, remained completely preserved in diabetic CTGF+/- mice. It thus appears that increased expression of CTGF decreases the turnover of the GBM by reduction of the MMP-activity, resulting in increased GBM thickness. So far the mechanism of this CTGF-dependent decrease in MMP-activity is unknown. Together, the data presented in this thesis indicate that CTGF is a pathogenic factor in diabetic tissue remodeling, and a potential marker and therapeutic target for prevention and treatment of DN. Currently, diabetic patients with microalbuminuria are being recruited for a clinical trial to assess whether treatment with a CTGF-neutralizing antibody can help to prevent progression to diabetic nephropathy or even revert microalbuminuria to normoalbuminuria
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