Nakagawa T
Division of Renal Disease and Hypertension, University of Colorado Denver, Aurora, CO 80045, USA.
Clin Nephrol. 2009 Feb;71(2):103-9. doi: 10.5414/cnp71103.
Diabetics develop a variety of histological abnormalities in the kidney. Early features include glomerular hypertrophy, glomerular basement membrane thickening, and mesangial expansion, whereas mesangiolysis, glomerular capillary aneurysm and nodular lesions develop in late phase. The goal of preventing diabetic nephropathy is important, but its achievement has been difficult due in part to a lack of an animal model for human diabetic nephropathy. Most animal models develop mild lesions in early phase diabetes, but not advanced lesions in late phase. Vascular endothelial growth factor (VEGF) mediates diabetic nephropathy, but its precise role remains to be determined. A complexity of VEGF function is that it is protective in nondiabetic renal diseases but is deleterious in diabetic nephropathy. Because diabetes is associated with endothelial dysfunction, we hypothesized that VEGF is deleterious in the setting of endothelial dysfunction. To test this hypothesis, we recently developed a new model of diabetic nephropathy in mice deficient in endothelial nitric oxide synthase (eNOS). Importantly, these mice developed the advanced lesions of diabetic nephropathy resembling to those in human diabetic nephropathy. In addition, these models also exhibit an uncoupling condition of VEGF with NO. In this review, we discuss our hypothesis which is that uncoupling of VEGF with NO causes advanced diabetic nephropathy.
糖尿病患者的肾脏会出现多种组织学异常。早期特征包括肾小球肥大、肾小球基底膜增厚和系膜扩张，而后期会出现系膜溶解、肾小球毛细血管动脉瘤和结节性病变。预防糖尿病肾病的目标很重要，但由于缺乏人类糖尿病肾病的动物模型，实现这一目标一直很困难。大多数动物模型在糖尿病早期会出现轻度病变，但在后期不会出现晚期病变。血管内皮生长因子（VEGF）介导糖尿病肾病，但其确切作用仍有待确定。VEGF功能的复杂性在于它在非糖尿病性肾脏疾病中具有保护作用，但在糖尿病肾病中具有有害作用。由于糖尿病与内皮功能障碍有关，我们推测VEGF在内皮功能障碍的情况下具有有害作用。为了验证这一假设，我们最近在缺乏内皮型一氧化氮合酶（eNOS）的小鼠中开发了一种新的糖尿病肾病模型。重要的是，这些小鼠出现了类似于人类糖尿病肾病的晚期病变。此外，这些模型还表现出VEGF与NO的解偶联状态。在这篇综述中，我们讨论了我们的假设，即VEGF与NO的解偶联导致晚期糖尿病肾病。
