Department of Nephrology, Medical School, University of Thessaly, Larissa, Greece.
Ren Fail. 2013;35(4):592-9. doi: 10.3109/0886022X.2013.773836. Epub 2013 Mar 11.
Diabetic nephropathy is the leading cause of end-stage renal disease. Diabetes mellitus is characterized by generalized endothelial dysfunction. However, recent data also emphasizes the role of local renal endothelium dysfunction in the pathogenesis of diabetic nephropathy. Hyperglycemia triggers a complex network of signal-transduction molecules, transcription factors, and mediators that culminate in endothelial dysfunction. In the glomerulus, vascular endothelial growth factor-A (VEGF)-induced neoangiogenesis may contribute to the initial hyperfiltration and microalbuminuria due to increased filtration area and immaturity of the neovessels, respectively. However, subsequent decrease in podocytes number decreases VEGF production resulting in capillary rarefaction and decreased glomerular filtration rate (GFR). Decreased nitric oxide availability also plays a significant role in the development of advanced lesions of diabetic nephropathy through disruption of glomerular autoregulation, uncontrolled VEGF action, release of prothrombotic substances by endothelial cells and angiotensin-II-independent aldosterone production. In addition, disturbances in endothelial glycocalyx contribute to decreased permselectivity and microalbuminuria; whereas there are recent evidences that reduced glomerular fenestral endothelium leads to decreased GFR levels. Endothelial repair mechanisms are also impaired in diabetes, since circulating endothelial progenitor cells number is decreased in diabetic patients with microalbuminuria. Finally, in the context of elevated profibrotic cytokine transforming growth factor-β levels, endothelial cells also confer to the deteriorating process of fibrosis in advanced diabetic nephropathy through endothelial to mesenchymal transition.
糖尿病肾病是终末期肾病的主要原因。糖尿病的特征是全身性内皮功能障碍。然而，最近的数据也强调了局部肾脏内皮功能障碍在糖尿病肾病发病机制中的作用。高血糖引发了一系列信号转导分子、转录因子和介质的复杂网络，最终导致内皮功能障碍。在肾小球中，血管内皮生长因子-A（VEGF）诱导的新生血管可能导致初始高滤过和微量白蛋白尿，分别是由于滤过面积增加和新生血管不成熟。然而，随后 podocytes 数量的减少会导致 VEGF 产生减少，从而导致毛细血管稀疏和肾小球滤过率（GFR）降低。一氧化氮供应的减少也通过破坏肾小球自身调节、不受控制的 VEGF 作用、内皮细胞释放促血栓物质和独立于血管紧张素-II 的醛固酮产生，在糖尿病肾病的晚期病变发展中起重要作用。此外，内皮糖萼的紊乱也导致了滤过选择性降低和微量白蛋白尿；而最近有证据表明，肾小球裂孔内皮的减少导致 GFR 水平降低。在升高的促纤维化细胞因子转化生长因子-β水平的情况下，内皮细胞也通过内皮向间充质转化，导致晚期糖尿病肾病纤维化的恶化过程。
