Pathogenetic mechanisms of diabetic nephropathy

Francesco P Schena, Loreto Gesualdo
Journal of the American Society of Nephrology: JASN 2005, 16 Suppl 1: S30-3
Diabetes is the leading cause of ESRD because diabetic nephropathy develops in 30 to 40% of patients. Diabetic nephropathy does not develop in the absence of hyperglycemia, even in the presence of a genetic predisposition. Multigenetic predisposition contributes in the development of diabetic nephropathy, thus supporting that many factors are involved in the pathogenesis of the disease. Hyperglycemia induces renal damage directly or through hemodynamic modifications. It induces activation of protein kinase C, increased production of advanced glycosylation end products, and diacylglycerol synthesis. In addition, it is responsible for hemodynamic alterations such as glomerular hyperfiltration, shear stress, and microalbuminuria. These alterations contribute to an abnormal stimulation of resident renal cells that produce more TGF-beta1. This growth factor upregulates GLUT-1, which induces an increased intracellular glucose transport and D-glucose uptake. TGF-beta1 causes augmented extracellular matrix protein deposition (collagen types I, IV, V, and VI; fibronectin, and laminin) at the glomerular level, thus inducing mesangial expansion and glomerular basement membrane thickening. However, low enzymatic degradation of extracellular matrix contributes to an excessive accumulation. Because hyperglycemia is the principal factor responsible for structural alterations at the renal level, glycemic control remains the main target of the therapy, whereas pancreas transplantation is the best approach for reducing the renal lesions.

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