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Mediators of Diabetic Renal Disease: The Case for TGF- as the Major Mediator

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

Correspondence to Dr. Fuad N. Ziyadeh, Renal-Electrolyte and Hypertension Division, University of Pennsylvania, 700 Clinical Research Building, 415 Curie Boulevard, Philadelphia, PA 19104-4218. Phone: 215-573-1837; Fax: 215-898-0189; E-mail: ziyadeh{at}mail.med.upenn.edu

ABSTRACT. The critical role of hyperglycemia in the genesis of diabetic nephropathy has been established by cell culture studies, experimental animal models, and clinical trials. Certain cytokines and growth factors have been identified as likely mediators of the effects of high ambient glucose on the kidney, but prominent among these is TGF-, a prototypical hypertrophic and fibrogenic cytokine. Overexpression of TGF- has been demonstrated in the glomerular and tubulointerstitial compartments of experimental diabetic animals. The TGF- receptor signaling system is also triggered, as evidenced by upregulation of the TGF- type II receptor and activation of the downstream Smad signaling pathway. Treatment of diabetic mice with neutralizing anti–TGF- antibodies prevents the development of renal hypertrophy, mesangial matrix expansion, and the decline in renal function. Antibody therapy also reverses the established lesions of diabetic glomerulopathy. These studies argue strongly in support of the hypothesis that overactivity of the TGF- system in the kidney is a crucial mediator of diabetic renal hypertrophy and mesangial matrix expansion.

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