At present, diabetic kidney disease affects about 15-25% of type 1 and 30 -40% of type 2 diabetic patients. Several decades of extensive research has elucidated various pathways to be implicated in the development of diabetic kidney disease. This review focuses on the metabolic factors beyond blood glucose that are involved in the pathogenesis of diabetic kidney disease, i.e., advanced glycation end-products and the aldose reductase system. Furthermore, the contribution of hemodynamic factors,

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... he renin-angiotensin system, the endothelin system, and the nitric oxide system, as well as the prominent role of the intracellular signaling molecule protein kinase C are discussed. Finally, the respective roles of TGF-␤, GH and IGFs, vascular endothelial growth factor, and plateletderived growth factor are covered. The complex interplay between these different pathways will be highlighted. A brief introduction to each system and description of its expression in the normal kidney is followed by in vitro, experimental, and clinical evidence addressing the role of the system in diabetic kidney disease. Finally, well-known and potential therapeutic strategies targeting each system are discussed, ending with an overall conclusion. (Endocrine Reviews 25: 971-1010, 2004) Ϫ