Biochemical events and cytokine interactions linking glucose metabolism to the development of diabetic nephropathy

Abstract

The important role of hyperglycemia in the genesis of diabetic renal disease has been strengthened by tissue culture studies, experimental animal models, and clinical trials. A mechanistic understanding of the cellular and biochemical processes that link hyperglycemia with the development of diabetic nephropathy is indispensable for directing the most optimal therapeutic interventions. Likely mediators of the effects of high ambient glucose include activation of the polyol pathway, increased protein kinase C activity, nonenzymatic glycation of circulating or matrix proteins, and/or aberrant synthesis or actions of cytokines and vasomodulatory agents. The latter include angiotensin II, thromboxane, platelet-derived growth factor, endothelins, insulin-like growth factor-1, and transforming growth factor-beta. The studies we review here argue strongly in support of the hypothesis that elevated production and/or activity of transforming growth factor-beta in the kidney is a final common mediator of diabetic renal hypertrophy and mesangial matrix expansion.