The pivotal role of VEGF on glomerular macrophage infiltration in advanced diabetic nephropathy
The pivotal role of VEGF on glomerular macrophage infiltration in advanced diabetic nephropathy
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DOI：
10.1038/labinvest.2008.60
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发表时间：
2008-09-01
影响因子：
5
通讯作者：
Nakagawa, Takahiko
中科院分区：
文献类型：
--
作者：
Sato, Waichi;Kosugi, Tomoki;Nakagawa, Takahiko
越来越多的证据表明炎症与糖尿病肾病的发展有关。我们最近报道了糖尿病内皮型一氧化氮合酶敲除（eNOS KO）小鼠发生类似人类糖尿病肾病的晚期肾小球病变。血管内皮生长因子（VEGF）是糖尿病肾病的主要因子，已知其对巨噬细胞具有趋化性。在此，我们研究了VEGF与实验性糖尿病肾病中巨噬细胞浸润的关系。与糖尿病C57 BL/ 6小鼠相比，糖尿病eNOS KO小鼠的肾小球巨噬细胞浸润显著增加，并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小鼠中受损肾小球中Flt- 1阳性巨噬细胞的浸润相关，表明VEGF可能有助于巨噬细胞迁移。在C57 BL/ 6和eNOS KO小鼠中，肾脏nNOS和iNOS表达均未改变。为了确定缺乏NO是否会影响巨噬细胞的VEGF活化，我们在体外研究中检测了外源性NO是否可以阻断VEGF诱导的巨噬细胞迁移。外源性NO阻断了巨噬细胞对VEGF的迁移和肥大。NO通过下调巨噬细胞上Flt- 1的表达来介导这些作用。总之，NO通过抑制Flt- 1表达负性调节VEGF诱导的巨噬细胞迁移。VEGF -内皮NO解偶联途径可能部分解释VEGF如何导致糖尿病肾小球疾病。
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.