Mediators of diabetic renal disease: the case for tgf-Beta as the major mediator

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-beta, a prototypical hypertrophic and fibrogenic cytokine. Overexpression of TGF-beta has been demonstrated in the glomerular and tubulointerstitial compartments of experimental diabetic animals. The TGF-beta receptor signaling system is also triggered, as evidenced by upregulation of the TGF-beta type II receptor and activation of the downstream Smad signaling pathway. Treatment of diabetic mice with neutralizing anti-TGF-beta 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-beta system in the kidney is a crucial mediator of diabetic renal hypertrophy and mesangial matrix expansion.