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

The critical role of hyperglycemia in the genesis of diabetic nephropathy has been established by cell culture stud- ies, 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 hypertro- phic 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 dia- betic mice with neutralizing anti-TGF- antibodies prevents the development of renal hypertrophy, mesangial matrix ex- pansion, and the decline in renal function. Antibody therapy also reverses the established lesions of diabetic glomerulopa- thy. 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. The structural renal changes in diabetes consist of glomer- ular and tubuloepithelial hypertrophy, followed by thickening of glomerular and tubular basement membranes and progres- sive accumulation of extracellular matrix proteins in the mes- angium and the interstitium. Identifying mediators of increased synthesis or decreased degradation of matrix molecules in diabetic renal disease may help design novel, effective thera- pies to avert glomerulosclerosis and tubulointerstitial fibrosis and the development of proteinuria and progressive renal insufficiency. TGF- is one effector molecule that has been studied ex-