Clinica Chimica Acta 297 (2000) 135–144 www.elsevier.com / locate / clinchim Review Molecular mechanism of diabetic nephropathy * Rainer Lehmann, Erwin D. Schleicher Department of Internal Medicine, Division of Endocrinology, Metabolism and Clinical Chemistry, ¨ ¨ ¨ University of Tubingen, Otfried-Muller-Straße 10, D-72076 Tubingen, Germany Received 20 October 1999; received in revised form 12 January 2000; accepted 10 February 2000 Abstract 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 b1 (TGF-b1) is induced and TGF-b1 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-b1 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-b1) was found in early diabetic nephropathy. However, the diagnostic value of these new parameters remains to be established.  2000 Elsevier Science B.V. All rights reserved. Keywords: Diabetic nephropathy; Tubular marker proteins; Matrix proteins; Cytokines; Molecular mechanism Abbreviations: ACE, angiotensin converting enzyme; AGE, advanced glucosylation end product; RAGE, receptor for advanced glucosylation end product; TGF-b, transforming growth factor-b; PKC, protein kinase C; DCCT, diabetes control and complication trial; UKPDS, United Kingdom prospective diabetes study *Corresponding author. Tel.: 1 49-7071-29-87599; fax: 1 49-7071-29-5974. E-mail address: enschlei@med.uni-tuebingen.de (E.D. Schleicher) 0009-8981 / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved. PII: S0009-8981(00)00240-0