Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792-4108, USA.
Am J Physiol Renal Physiol. 2013 Jan 1;304(1):F19-30. doi: 10.1152/ajprenal.00036.2012. Epub 2012 Oct 17.
Diabetic nephropathy is the most common cause of end-stage renal disease and is a major risk factor for cardiovascular disease. In the United States, microvascular complications during diabetic nephropathy contribute to high morbidity and mortality rates. However, the cell-autonomous impact of diabetes on kidney endothelial cell function requires further investigation. Male Akita/+ [autosomal dominant mutation in the insulin II gene (Ins2)] mice reproducibly develop diabetes by 4 wk of age. Here, we examined the impact a short duration of diabetes had on kidney endothelial cell function. Kidney endothelial cells were prepared from nondiabetic and diabetic mice (4 wk of diabetes) to delineate the early changes in endothelial cell function. Kidney endothelial cells from Akita/+ mice following 4 wk of diabetes demonstrated aberrant expression of extracellular matrix proteins including decreased osteopontin and increased fibronectin expression which correlated with increased α5-integrin expression. These changes were associated with the attenuation of migration and capillary morphogenesis. Kidney endothelial cells from Akita/+ mice had decreased VEGF levels but increased levels of endothelial nitric oxide synthase(eNOS) and NO, suggesting uncoupling of VEGF-mediated NO production. Knocking down eNOS expression in Akita/+ kidney endothelial cells increased VEGF expression, endothelial cell migration, and capillary morphogenesis. Furthermore, attenuation of sprouting angiogenesis of aortas from Akita/+ mice with 8 wk of diabetes was restored in the presence of the antioxidant N-acetylcysteine. These studies demonstrate that aberrant endothelial cell function with a short duration of diabetes may set the stage for vascular dysfunction and rarefaction at later stages of diabetes.
糖尿病肾病是终末期肾病的最常见原因，也是心血管疾病的主要危险因素。在美国，糖尿病肾病的微血管并发症导致高发病率和死亡率。然而，糖尿病对肾脏内皮细胞功能的细胞自主性影响需要进一步研究。雄性 Akita/+ [胰岛素 II 基因（Ins2）的常染色体显性突变] 小鼠在 4 周龄时可重现性地发生糖尿病。在这里，我们研究了短期糖尿病对肾脏内皮细胞功能的影响。从非糖尿病和糖尿病（4 周糖尿病）小鼠中分离出肾脏内皮细胞，以描绘内皮细胞功能的早期变化。在糖尿病 4 周后，Akita/+ 小鼠的肾脏内皮细胞表现出细胞外基质蛋白的异常表达，包括骨桥蛋白减少和纤连蛋白表达增加，这与α5-整合素表达增加有关。这些变化与迁移和毛细血管形态发生的减弱有关。Akita/+ 小鼠的肾脏内皮细胞 VEGF 水平降低，但内皮型一氧化氮合酶（eNOS）和 NO 水平升高，表明 VEGF 介导的 NO 产生失偶联。在 Akita/+ 肾脏内皮细胞中敲低 eNOS 表达可增加 VEGF 表达、内皮细胞迁移和毛细血管形态发生。此外，在抗氧化剂 N-乙酰半胱氨酸存在的情况下，可恢复糖尿病 8 周的 Akita/+ 小鼠主动脉发芽血管生成的减弱。这些研究表明，短暂的糖尿病会导致内皮细胞功能异常，为糖尿病后期的血管功能障碍和稀疏奠定基础。
