Gealekman Olga, Brodsky Sergey V, Zhang Fan, Chander Praveen N, Friedli Caline, Nasjletti Alberto, Goligorsky Michael S
Departments of Medicine, Pathology, and Pharmacology, New York Medical College, Valhalla, New York, USA.
Kidney Int. 2004 Dec;66(6):2337-47. doi: 10.1111/j.1523-1755.2004.66035.x.
Progression of nephropathy in metabolic syndrome is associated with microvasculopathy and vascular dropout.
Eight- and 22-week-old Zucker diabetic fat (ZDF) and Zucker lean (ZL) rats were studied to characterize the progression of nephropathy, and to test the effect of a peroxynitrite scavenger, Ebselen, on renal microvasculature and angiogenic competence.
Capillary density was increased, both in the cortex (P < 0.05) and in the inner medulla (P < 0.001) by the age of 8 weeks, but significantly decreased (P < 0.01 and P < 0.001) by the age of 22 weeks in ZDF compared to ZL rats. Similarly, the angiogenic competence of cortical and medullary renal explants was increased in 8-week-old ZDF (P < 0.01), but decreased at 22 weeks (P < 0.001). Alterations of angiogenic competence in ZDF rats were associated with altered expression of vascular endothelial growth factor (VEGF), reduced expression of Flk-1, and neuropilin. Acetylcholine-induced relaxation of microdissected interlobar arteries from 8-week-old ZDF rats was unimpaired, but significantly attenuated in 22-week-old ZDF rats (P < 0.001). Treatment with Ebselen partially prevented the decrease in capillary density and angiogenic competence of renal explants, and restored acetylcholine-induced vasorelaxation in 22-week-old ZDF rats.
The progression of nephropathy in ZDF rats is associated with decreased angiogenic competence both ex vivo and in vivo. This is accompanied by a altered expression of VEGF system components and endothelial dysfunction, and scavenging peroxynitrite with Ebselen ameliorates the progression of microvasculopathy and partially restores angiogenesis. These findings reveal the complex mechanism of microvascular dropout in experimental metabolic syndrome.
代谢综合征中肾病的进展与微血管病变和血管缺失有关。
对8周龄和22周龄的Zucker糖尿病肥胖（ZDF）大鼠和Zucker瘦（ZL）大鼠进行研究，以表征肾病的进展，并测试过氧亚硝酸盐清除剂依布硒啉对肾微血管系统和血管生成能力的影响。
与ZL大鼠相比，ZDF大鼠在8周龄时皮质（P < 0.05）和髓质内层（P < 0.001）的毛细血管密度均增加，但在22周龄时显著降低（P < 0.01和P < 0.001）。同样，8周龄ZDF大鼠皮质和髓质肾外植体的血管生成能力增加（P < 0.01），但在22周龄时降低（P < 0.001）。ZDF大鼠血管生成能力的改变与血管内皮生长因子（VEGF）表达改变、Flk-1表达降低和神经纤毛蛋白有关。8周龄ZDF大鼠微分离叶间动脉对乙酰胆碱诱导的舒张未受影响，但在22周龄ZDF大鼠中显著减弱（P < 0.001）。依布硒啉治疗部分预防了肾外植体毛细血管密度和血管生成能力的降低，并恢复了22周龄ZDF大鼠乙酰胆碱诱导的血管舒张。
ZDF大鼠肾病的进展与体内外血管生成能力降低有关。这伴随着VEGF系统成分表达的改变和内皮功能障碍，用依布硒啉清除过氧亚硝酸盐可改善微血管病变的进展并部分恢复血管生成。这些发现揭示了实验性代谢综合征中微血管缺失的复杂机制。
