TGF-beta: a crucial component of the pathogenesis of diabetic nephropathy.

In summary, metabolic, hemodynamic, and genetic factors are all important in the development and progression of diabetic nephropathy (33). Recent studies using cell culture techniques and experimental animal models have provided important insight into the role of hyperglycemia in this disease. The nature of the factors directly arising as a consequence of hyperglycemia and the steps involved in diabetic complications are not completely understood. The characteristic lesions of diabetic nephropathy may be intimately related to the effects of high ambient glucose on intracellular signaling events, various growth factors/cytokines, and nonenzymatic glycation of proteins (36). The growth factor TGF-beta has emerged as a key participant in the cascade of events which leads to kidney sclerosis. Increased TGF-beta expression in the kidney in diabetes mellitus mediates the renal actions of high ambient glucose to promote cellular hypertrophy and stimulate extracellular matrix biosynthesis. Neutralizing the actions of TGF-beta with highly specific monoclonal antibodies or with application of antisense technology can effectively prevent the induction of the kidney lesions of diabetes in mice independent of any changes in blood glucose levels. Such maneuvers are crucial for establishing proof-of-concept and Koch's postulates (17), but they are still far removed from clinical applicability. Nevertheless, it is hoped that further studies to elucidate the efficacy of novel interventions to intercept the activity of the renal TGF-beta system will prove useful for effectively halting the progression of diabetic nephropathy.