Diabetic nephropathy and transforming growth factor-beta: transforming our view of glomerulosclerosis and fibrosis build-up.

The manifestations of diabetic nephropathy may be a consequence of the actions of certain cytokines and growth factors. Prominent among these is transforming growth factor beta (TGF-beta) because it promotes renal cell hypertrophy and stimulates extracellular matrix accumulation, the 2 hallmarks of diabetic renal disease. In tissue culture studies, cellular hypertrophy and matrix production are stimulated by high glucose concentrations in the culture media. High glucose, in turn, appears to act through the TGF-beta system because high glucose increases TGF-beta expression, and the hypertrophic and matrix-stimulatory effects of high glucose are prevented by anti-TGF-beta therapy. In experimental diabetes mellitus, several reports describe overexpression of TGF-beta or TGF-beta type II receptor in the glomerular and tubulointerstitial compartments. As might be expected, the intrarenal TGF-beta system is triggered, evidenced by activity of the downstream Smad signaling pathway. Treatment of diabetic animals with a neutralizing anti-TGF-beta antibody prevents the development of mesangial matrix expansion and the progressive decline in renal function. This antibody therapy also reverses the established lesions of diabetic glomerulopathy. Finally, the renal TGF-beta system is significantly up-regulated in human diabetic nephropathy. Although the kidney of a nondiabetic subject extracts TGF-beta1 from the blood, the kidney of a diabetic patient actually elaborates TGF-beta1 protein into the circulation. Along the same line, an increased level of TGF-beta in the urine is associated with worse clinical outcomes. In concert with TGF-beta, other metabolic mediators such as connective tissue growth factor and reactive oxygen species promote the accumulation of excess matrix. This fibrotic build-up also occurs in the tubulointerstitium, probably as the result of heightened TGF-beta activity that stimulates tubular epithelial and interstitial fibroblast cells to overproduce matrix. The data presented here strongly support the consensus that the TGF-beta system mediates the renal hypertrophy, glomerulosclerosis, and tubulointerstitial fibrosis of diabetic kidney disease.