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

Abstract

Progressive renal injury in diabetes mellitus leads to majormorbidity and mortality. The manifestations of diabetic nephropathy may bea consequence of the actions of certain cytokines and growth factors. Prominentamong these is transforming growth factor-beta (TGF-β) because it promotesrenal cell hypertrophy and stimulates extracellular matrix accumulation, thetwo hallmarks of diabetic renal disease. In cell culture, high ambient glucoseincreases TGF-β m RNA and protein in proximal tubular, glomerular epithelial,and mesangial cells. Neutralizing anti-TGF-β antibodies prevent the hypertrophicand matrix stimulatory effects of high glucose in these cells. In experimentaland human diabetes mellitus, several reports describe overexpression of TGF-βin the glomeruli and tubulointerstitium. We demonstrate that short-term treatmentof diabetic mice with neutralizing monoclonal antibodies against TGF-βsignificantly reduces kidney weight and glomerular hypertrophy and attenuatesthe increase in extracellular matrix mRNAs. Long-term treatment of diabeticmice further improves the renal pathology and also ameliorates the functionalabnormalities of diabetic nephropathy. Finally, we provide evidence that therenal TGF-β system is significantly up-regulated in human diabetes. Thekidney of a diabetic patient actually elaborates TGF-β1 protein intothe circulation whereas the kidney of a non-diabetic subject extracts TGF-β1from the circulation. The data we review here strongly support the hypothesisthat elevated production or activity of the TGF-β system mediates diabeticrenal hypertrophy and extracellular