Involvement of the transforming growth factor-ß system in the pathogenesis of diabetic nephropathy.

ABSTRACT

The manifestation of diabetic nephropathy may be a consequence of the actions of certain cytokines and growth factors. Prominent among them is transforming growth factor-ß (TGF-ß), which promotes renal cell hypertrophy and stimulates extracellular matrix accumulation, the two hallmarks of diabetic renal disease. In experimental and human diabetes mellitus, several reports describe overexpression of TGF-ß in the glomeruli and tubulointerstitium. In renal cell cultures, hypertrophy and matrix production are stimulated by high glucose concentrations in the culture media. High glucose, in turn, appears to act through the TGF-ß system; high glucose increases TGF-ß expression, and the hypertrophic and matrix stimulatory effects of high glucose are prevented by anti-TGF-ß therapy. Short-term treatment with the same neutralizing monoclonal antibodies against TGF-ß in type 1 diabetic mice significantly reduces kidney weight and glomerular hypertrophy and attenuates the increase in extracellular matrix mRNA. Similar treatment of type 2 diabetic mice in the long term further diminishes the renal pathology and ameliorates the functional abnormalities of diabetic nephropathy. Finally, the intrarenal TGF-ß system is significantly up-regulated in human diabetes. Whereas the kidney of a nondiabetic subject extracts TGF-ß1 from the circulation, the kidney of a diabetic patient elaborates TGF-ß1 protein into the circulation. The data we review here strongly support the hypothesis that elevated production or activity of the TGF-ß system mediates diabetic renal hypertrophy and extracellular matrix expansion.