Potential role of TGF-β in diabetic nephropathy

Renal injury in diabetes mellitus is a major cause of morbidity and mortality. Several manifestations of diabetic nephropathy may be a consequence of altered production and/or response to cytokines or growth factors, Transforming growth factor-beta (TGF-beta) is one such factor because it promotes renal cell hypertrophy and regulates the production of extracellular matrix molecules. In addition, high ambient glucose increases TGF-beta 1 mRNA and protein level in cultured proximal tubular cells and glomerular epithelial and mesangial cells. Neutralizing anti-TGF-beta antibodies or antisense TGF-beta 1 oligodeoxynucleotides prevents the hypertrophic effects of high glucose and the stimulation of matrix synthesis in renal cells, Several reports have described overexpression of TGF-beta in the glomeruli and tubulointerstitium of experimental and human diabetes mellitus, We recently provided evidence that the kidney in diabetic patients displays net renal production of immunoreactive TGF-beta 1, whereas there is net renal extraction in nondiabetic subjects. We also demonstrated that short-term treatment of streptozotocin-diabetic mice with neutralizing monoclonal antibody directed against TGF-beta significantly reduces kidney weight and glomerular hypertrophy, and attenuates the increase in extracellular matrix mRNA levels, The factors that mediate increased renal TGF-beta activity involve hyperglycemia per se and the intermediary action of other potent mediators such as angiotensin II, thromboxane, endothelins, and platelet-derived growth factor.