Transforming Growth Factor And Other Cytokines In Experimental And Human Diabetic Nephropathy

Belinda Jim, Sheldon Chen, and Fuad N. Ziyadeh

Penn Center for Molecular Studies of Kidney Diseases, Renal-Electrolyte and Hypertension Division, Department of Medicine, University of Pennsylvania Philadelphia, PA, USA

Genetic, hemodynamic, and metabolic factors are important in the pathogenesis of diabetic nephropathy. This chapter, complementing the coverage of related chapters in this book, will focus on some of the metabolic mediators, especially the various cytokines and growth factors, with particular focus on the transforming growth factor-^ (TGF-P) system. Various mediator factors and signal transduction pathways interact in an intricate circuitry of autocrine, paracrine, or even endocrine mechanisms when the kidney is chronically exposed to high ambient glucose concentrations. The effects of high glucose on renal cells may arise as a consequence of increased flux of glucose metabolism through the polyol pathway [1], increased de novo synthesis of diacylglycerol (DAG) with subsequent activation of protein kinase C (PKC) [2, 3], activation of the hexosamine pathway [4], and increased non-enzymatic glycation of proteins [5, 6]. Recent studies have demonstrated the importance of many soluble mediators in diabetic renal disease (reviewed in [7, 8]), including platelet-derived growth factor (PDGF), endothelin, angiotensin II (AngII), prostanoids, leptin, and vascular endothelial growth factor (VEGF). Some features of these mediators will be highlighted here, after providing a detailed account of the crucial role that TGF-P plays in the pathogenesis of diabetic nephropathy. Additionally, the discussion will summarize the evidence linking

Mogensen CE (ed.) THE KIDNEY AND HYPERTENSION IN DIABETES MELLITUS. Copyright© 2004 by Martin Dunitz, a member of the Taylor & Francis Group, plc. All rights reserved.

the diverse mediators to the overactivity of the TGF-P system in diabetic renal disease.

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