Chen Sheldon, Jim Belinda, Ziyadeh Fuad N
Department of Medicine, University of Philadelphia, PA 19104, USA.
Semin Nephrol. 2003 Nov;23(6):532-43. doi: 10.1053/s0270-9295(03)00132-3.
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-beta) because it promotes renal cell hypertrophy and stimulates extracellular matrix accumulation, the 2 hallmarks of diabetic renal disease. In tissue culture studies, cellular hypertrophy and matrix production are stimulated by high glucose concentrations in the culture media. High glucose, in turn, appears to act through the TGF-beta system because high glucose increases TGF-beta expression, and the hypertrophic and matrix-stimulatory effects of high glucose are prevented by anti-TGF-beta therapy. In experimental diabetes mellitus, several reports describe overexpression of TGF-beta or TGF-beta type II receptor in the glomerular and tubulointerstitial compartments. As might be expected, the intrarenal TGF-beta system is triggered, evidenced by activity of the downstream Smad signaling pathway. Treatment of diabetic animals with a neutralizing anti-TGF-beta antibody prevents the development of mesangial matrix expansion and the progressive decline in renal function. This antibody therapy also reverses the established lesions of diabetic glomerulopathy. Finally, the renal TGF-beta system is significantly up-regulated in human diabetic nephropathy. Although the kidney of a nondiabetic subject extracts TGF-beta1 from the blood, the kidney of a diabetic patient actually elaborates TGF-beta1 protein into the circulation. Along the same line, an increased level of TGF-beta in the urine is associated with worse clinical outcomes. In concert with TGF-beta, other metabolic mediators such as connective tissue growth factor and reactive oxygen species promote the accumulation of excess matrix. This fibrotic build-up also occurs in the tubulointerstitium, probably as the result of heightened TGF-beta activity that stimulates tubular epithelial and interstitial fibroblast cells to overproduce matrix. The data presented here strongly support the consensus that the TGF-beta system mediates the renal hypertrophy, glomerulosclerosis, and tubulointerstitial fibrosis of diabetic kidney disease.
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），因为它促进肾细胞肥大并刺激细胞外基质积聚，这是糖尿病肾病的两个主要特征。在组织培养研究中，培养基中的高葡萄糖浓度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，因为高葡萄糖会增加TGF-β的表达，而抗TGF-β治疗可阻止高葡萄糖的肥大和基质刺激作用。在实验性糖尿病中，有几份报告描述了肾小球和肾小管间质区室中TGF-β或II型TGF-β受体的过度表达。正如预期的那样，肾内TGF-β系统被触发，下游Smad信号通路的活性证明了这一点。用中和性抗TGF-β抗体治疗糖尿病动物可防止系膜基质扩张的发展和肾功能的逐渐下降。这种抗体疗法还可逆转已形成的糖尿病肾小球病变。最后，在人类糖尿病肾病中，肾TGF-β系统明显上调。虽然非糖尿病患者的肾脏从血液中提取TGF-β1，但糖尿病患者的肾脏实际上会将TGF-β1蛋白释放到循环中。同样，尿液中TGF-β水平的升高与更差的临床结果相关。与TGF-β协同作用，其他代谢介质如结缔组织生长因子和活性氧会促进过量基质的积累。这种纤维化的形成也发生在肾小管间质，可能是由于TGF-β活性增强，刺激肾小管上皮细胞和间质成纤维细胞过度产生基质。此处提供的数据有力地支持了这样一种共识，即TGF-β系统介导了糖尿病肾病的肾肥大、肾小球硬化和肾小管间质纤维化。
