Penn Center for Molecular Studies of Kidney Diseases, Renal-Electrolyte and Hypertension Division, Department of Medicine, University of Pennsylvania, 700 Clinical Research Building, 415 Curie Boulevard, Philadelphia, PA 19104-4218, USA Tel. +1-215-573-1837; Fax +1-215-898-0189 e-mail:
Clin Exp Nephrol. 2002 Sep;6(3):125-9. doi: 10.1007/s101570200021.
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-β (TGF-β), 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-β 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-β system; high glucose increases TGF-β expression, and the hypertrophic and matrix stimulatory effects of high glucose are prevented by anti-TGF-β therapy. Short-term treatment with the same neutralizing monoclonal antibodies against TGF-β 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-β system is significantly up-regulated in human diabetes. Whereas the kidney of a nondiabetic subject extracts TGF-β1 from the circulation, the kidney of a diabetic patient elaborates TGF-β1 protein into 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.
糖尿病肾病的表现可能是某些细胞因子和生长因子作用的结果。其中突出的是转化生长因子-β（TGF-β），它促进肾细胞肥大，并刺激细胞外基质的积累，这是糖尿病肾病的两个标志。在实验性和人类糖尿病中，有几项报告描述了 TGF-β在肾小球和肾小管间质中的过度表达。在肾细胞培养物中，高浓度的葡萄糖会刺激细胞肥大和基质产生。反过来，高葡萄糖似乎通过 TGF-β系统起作用；高葡萄糖增加 TGF-β的表达，而抗 TGF-β治疗可预防高葡萄糖对细胞肥大和基质刺激的作用。在 1 型糖尿病小鼠中短期给予针对 TGF-β的同种型中和单克隆抗体治疗可显著降低肾脏重量和肾小球肥大，并减轻细胞外基质 mRNA 的增加。在长期内对 2 型糖尿病小鼠进行类似的治疗进一步减少了肾脏病理，并改善了糖尿病肾病的功能异常。最后，在人类糖尿病中，肾内 TGF-β系统显著上调。虽然非糖尿病患者的肾脏从循环中提取 TGF-β1，但糖尿病患者的肾脏会将 TGF-β1 蛋白分泌到循环中。我们在这里回顾的这些数据强烈支持这样一种假说，即升高的 TGF-β系统的产生或活性介导了糖尿病肾肥大和细胞外基质扩张。
