Molecular mechanism of diabetic nephropathy

R Lehmann, E D Schleicher
Clinica Chimica Acta; International Journal of Clinical Chemistry 2000, 297 (1): 135-44
Diabetic nephropathy is one of the main causes of renal end-stage disease. Morphologically, the development of diabetic nephropathy is characterized by progressive thickening of the glomerular basement membrane and by expansion of the mesangial matrix which correlates to glomerular filtration function. In vitro studies with cultured mesangial cells revealed that elevated glucose concentrations increase collagen synthesis similar to the in vivo situation. These studies showed that hyperglycemia may be toxic either by non-enzymatic reaction of glucose with proteins and subsequent formation of advanced glucosylation end products or by increased metabolism leading to increased oxidative stress and activation of protein kinase C resulting in increased production of cytokines. Particularly, de novo synthesis of transforming growth factor beta1 (TGF-beta1) is induced and TGF-beta1 appears also involved since blockage of this prosclerotic factor inhibits high glucose-induced collagen synthesis. Interestingly, it could be demonstrated that angiotensin II also stimulates TGF-beta1 production possibly via the same signal transduction pathway. Besides the classical clinical chemical parameters for evaluation of renal function, the measurement of urinary albumin excretion is now widely used for detection of developing diabetic nephropathy. Since diabetes causes glomerular and tubular changes, tubular marker proteins may be used to detect early renal damage. An increased urinary excretion of matrix proteins (e.g. collagen) and cytokines (e.g. TGF-beta1) was found in early diabetic nephropathy. However, the diagnostic value of these new parameters remains to be established.

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