Division of Renal Disease and Hypertension, University of Colorado Denver, 12700 East 19th Avenue, Aurora, CO 80045, USA.
Nat Rev Nephrol. 2011 Jan;7(1):36-44. doi: 10.1038/nrneph.2010.152. Epub 2010 Nov 2.
The mechanisms that drive the development of diabetic nephropathy remain undetermined. Only 30-40% of patients with diabetes mellitus develop overt nephropathy, which suggests that other contributing factors besides the diabetic state are required for the progression of diabetic nephropathy. Endothelial dysfunction is associated with human diabetic nephropathy and retinopathy, and advanced diabetic glomerulopathy often exhibits thrombotic microangiopathy, including glomerular capillary microaneurysms and mesangiolysis, which are typical manifestations of endothelial dysfunction in the glomerulus. Likewise, diabetic mice with severe endothelial dysfunction owing to deficiency of endothelial nitric oxide synthase develop progressive nephropathy and retinopathy similar to the advanced lesions observed in humans with diabetes mellitus. Additionally, inhibitors of the renin-angiotensin system fail to be renoprotective in some individuals with diabetic nephropathy (due in part to aldosterone breakthrough) and in some mouse models of the disease. In this Review, we discuss the clinical and experimental evidence that supports a role for endothelial nitric oxide deficiency and subsequent endothelial dysfunction in the progression of diabetic nephropathy and retinopathy. If endothelial dysfunction is the key factor required for diabetic nephropathy, then agents that improve endothelial function or raise intraglomerular nitric oxide level could be beneficial in the treatment of diabetic nephropathy.
导致糖尿病肾病发展的机制仍未确定。只有 30-40%的糖尿病患者出现显性肾病，这表明除糖尿病状态外，还需要其他因素促进糖尿病肾病的进展。内皮功能障碍与人类糖尿病肾病和视网膜病变有关，晚期糖尿病肾小球病变常表现为血栓性微血管病，包括肾小球毛细血管微动脉瘤和系膜溶解，这是肾小球内皮功能障碍的典型表现。同样，由于内皮型一氧化氮合酶缺乏导致严重内皮功能障碍的糖尿病小鼠会发展出进行性肾病和视网膜病变，类似于在糖尿病患者中观察到的晚期病变。此外，在一些糖尿病肾病患者（部分原因是醛固酮突破）和一些糖尿病小鼠模型中，肾素-血管紧张素系统抑制剂不能起到肾保护作用。在这篇综述中，我们讨论了支持内皮一氧化氮缺乏和随后内皮功能障碍在糖尿病肾病和视网膜病变进展中的作用的临床和实验证据。如果内皮功能障碍是糖尿病肾病发生的关键因素，那么改善内皮功能或提高肾小球内一氧化氮水平的药物可能对糖尿病肾病的治疗有益。
