The key role of the transforming growth factor-β 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 these is transforming growth factor-beta (TGF-β) 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-β mRNA and protein in proximal tubular, glomerular epithelial, and mesangial cells. Neutralizing anti-TGF-β antibodies prevent the hypertrophic and matrix stimulatory effects of high glucose in these cells. In experimental and human diabetes mellitus, several reports describe overexpression of TGF-β in the glomeruli and tubulointerstitium. We demonstrate that short-term treatment of diabetic mice with neutralizing monoclonal antibodies against TGF-β significantly reduces kidney weight and glomerular 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-β system is significantly up-regulated in human diabetes. The kidney of a diabetic patient actually elaborates TGF-β1 protein into the circulation whereas the kidney of a non-diabetic subject extracts TGF-β1 from the circulation. The data we review here strongly support the hypothesis that elevated production or activity of the TGF-β system mediates diabetic renal hypertrophy and extracellular matrix expansion.