Sato Waichi, Kosugi Tomoki, Zhang Li, Roncal Carlos A, Heinig Marcelo, Campbell-Thompson Martha, Yuzawa Yukio, Atkinson Mark A, Grant Maria B, Croker Byron P, Nakagawa Takahiko
Division of Nephrology, Department of Medicine, University of Florida, Gainesville, FL 32610-0224, USA.
Lab Invest. 2008 Sep;88(9):949-61. doi: 10.1038/labinvest.2008.60. Epub 2008 Jul 7.
A growing body of evidence implicates inflammation in the development of diabetic nephropathy. We recently reported that diabetic endothelial nitric oxide synthase knockout (eNOS KO) mice develop advanced glomerular lesions resembling human diabetic nephropathy. Vascular endothelial growth factor (VEGF) is a major factor in diabetic nephropathy, and is known to be chemotactic for macrophages. Herein, we examined the association of VEGF with macrophage infiltration in experimental diabetic nephropathy. Glomerular macrophage infiltration was markedly increased in diabetic eNOS KO mice compared to diabetic C57BL/6 mice, and correlated with glomerular injury, such as mesangiolysis, glomerular microaneurysm and nodular lesions of glomerular sclerosis. An elevation of podocyte VEGF expression correlated with infiltration of Flt-1-positive macrophage in injured glomeruli in diabetic eNOS KO mice, suggesting that VEGF could contribute to macrophage migration. Neither renal nNOS nor iNOS expression was altered in both C57BL/6 and eNOS KO mice. To determine if lack of NO could affect VEGF activation of macrophages, we examined if exogenous NO can block macrophage migration induced by VEGF in in vitro studies. Exogenous NO blocked macrophage migration and hypertrophy in response to VEGF. NO mediated these effects in part by downregulating Flt-1 expression on the macrophage. In summary, NO negatively regulates VEGF-induced macrophage migration by inhibiting Flt-1 expression. The VEGF-endothelial NO uncoupling pathway might partially explain how VEGF causes glomerular disease in diabetes.
越来越多的证据表明炎症与糖尿病肾病的发生发展有关。我们最近报道，糖尿病内皮型一氧化氮合酶基因敲除（eNOS KO）小鼠会出现类似于人类糖尿病肾病的晚期肾小球病变。血管内皮生长因子（VEGF）是糖尿病肾病中的一个主要因素，已知其对巨噬细胞具有趋化作用。在此，我们研究了实验性糖尿病肾病中VEGF与巨噬细胞浸润之间的关联。与糖尿病C57BL/6小鼠相比，糖尿病eNOS KO小鼠的肾小球巨噬细胞浸润明显增加，且与肾小球损伤相关，如系膜溶解、肾小球微动脉瘤和肾小球硬化的结节性病变。足细胞VEGF表达的升高与糖尿病eNOS KO小鼠受损肾小球中Flt-1阳性巨噬细胞的浸润相关，提示VEGF可能促进巨噬细胞迁移。在C57BL/6和eNOS KO小鼠中，肾脏nNOS和iNOS的表达均未改变。为了确定NO的缺乏是否会影响巨噬细胞的VEGF激活，我们在体外研究中检测了外源性NO是否能阻断VEGF诱导的巨噬细胞迁移。外源性NO可阻断巨噬细胞对VEGF的迁移和肥大反应。NO部分通过下调巨噬细胞上的Flt-1表达介导这些作用。总之，NO通过抑制Flt-1表达对VEGF诱导的巨噬细胞迁移起负调节作用。VEGF-内皮型NO解偶联途径可能部分解释了VEGF在糖尿病中如何导致肾小球疾病。
