The key role of the transforming growth factor-beta system in the pathogenesis of diabetic nephropathy

Progressive renal injury in diabetes mellitus leads to major morbidity and mortality. The manifestations of diabetic nephropathy may be a consequence of the actions of certain cytokines and growth factors. Prominent among the se is transforming growth factor-beta (TGF-beta) because it promotes renal cell hypertrophy and stimulates extracellular matrix accumulation, the two hallmarks of diabetic renal disease. In cell culture, high ambient glucose increases TGF-beta mRNA and protein in proximal tubular, glomerular epithel ial, and mesangial cells. Neutralizing anti-TGF-beta antibodies prevent the hypertrophic and matrix stimulatory effects of high glucose in these cells . In experimental and human diabetes mellitus, several reports describe ove rexpressian of TGF-beta in the glomcruli and tubulointerstitium. We demonst rate that short-term treatment of diabetic mice with neutralizing monoclona l antibodies against TGF-beta significantly reduces kidney weight and glome rular hypertrophy and attenuates the increase in extracellular matrix mRNAs . Long-term treatment of diabetic mice further improves the renal pathology and also ameliorates the functional abnormalities of diabetic nephropathy. Finally, we provide evidence that the renal TGF-beta system is significant ly up-regulated in human diabetes. The kidney of a diabetic patient actuall y elaborates TGF-beta1 protein into the circulation whereas the kidney of a non-diabetic subject extracts TGF-beta1 from the circulation. The data we review here strongly support the hypothesis that elevated production or act ivity of the TGF-beta system mediates diabetic renal hypertrophy and extrac ellular matrix expansion.