Molecular mechanism of diabetic nephropathy

Diabetic nephropathy is one of the main causes of renal end-stage disease. Morphologically, the development of diabetic nephropathy is characterized b y progressive thickening of the glomerular basement membrane and by expansi on of the mesangial matrix which correlates to glomerular filtration functi on. In vitro studies with cultured mesangial cells revealed that elevated g lucose concentrations increase collagen synthesis similar to the in vivo si tuation. These studies showed that hyperglycemia may be toxic either by non -enzymatic reaction of glucose with proteins and subsequent formation of ad vanced glucosylation end products or by increased metabolism leading to inc reased oxidative stress and activation of protein kinase C resulting in inc reased production of cytokines. Particularly, de novo synthesis of transfor ming growth factor beta 1 (TGF-beta 1) is induced and TGF-beta 1 appears al so involved since blockage of this prosclerotic factor inhibits high glucos e-induced collagen synthesis. Interestingly, it could be demonstrated that angiotensin II also stimulates TGF-beta 1 production possibly via the same signal transduction pathway. Besides the classical clinical chemical parame ters for evaluation of renal function, the measurement of urinary albumin e xcretion is now widely used for detection of developing diabetic nephropath y. Since diabetes causes glomerular and tubular changes, tubular marker pro teins may be used to detect early renal damage. An increased urinary excret ion of matrix proteins (e.g. collagen) and cytokines (e.g. TGF-beta 1) was found in early diabetic nephropathy. However, the diagnostic value of these new parameters remains to be established. (C) 2000 Elsevier Science B.V. A ll rights reserved.