Gremlin regulates renal inflammation via the vascular endothelial growth factor receptor 2 pathway
Gremlin regulates renal inflammation via the vascular endothelial growth factor receptor 2 pathway
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DOI：
10.1002/path.4537
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发表时间：
2015-08-01
影响因子：
7.3
通讯作者：
Ruiz-Ortega, Marta
中科院分区：
文献类型：
--
作者：
Lavoz, Carolina;Alique, Matilde;Ruiz-Ortega, Marta
炎症是进展性肾病的一个主要特征。Gremlin与骨形态发生蛋白(BMPs)结合，作为拮抗剂，调节肾脏形成和纤维化等过程。Gremlin还与血管内皮细胞中的血管内皮生长因子受体-2(VEGFR2)结合，诱导血管生成。在肾细胞中，gremlin调节增殖和纤维化，但没有与炎症相关的事件的数据。我们已经研究了Gremlin对肾脏的直接影响，评估了VEGFR2是否是一个功能性的gremlin受体。给小鼠肾脏注射重组gremlin可诱导位于近端肾小管上皮细胞的VEGFR2信号的快速和持续激活。Gremlin在体外与这些细胞中的VEGFR2结合，激活这一信号通路，而不依赖于其作为BMPs拮抗剂的作用。在体内，gremlin导致早期肾脏损伤，其特征是核因子(NF)-B途径激活，与促炎因子上调和免疫炎症细胞渗透有关。阻断VEGFR2可减轻小鼠肾脏炎症反应。体外实验证实gremlin/VEGFR2与核因子-B/炎症之间存在联系。在人类肾脏疾病和单侧输尿管梗阻实验模型中，gremlin的过度表达与VEGFR2的激活有关，在单侧输尿管梗阻的实验模型中，VEGFR2激酶的抑制可以减轻肾脏炎症。我们的数据显示，Gremlin/VEGFR2轴参与了肾脏炎症，并可能成为肾脏疾病的新靶点。版权所有(C)2015年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
Inflammation is a main feature of progressive kidney disease. Gremlin binds to bone morphogenetic proteins (BMPs), acting as an antagonist and regulating nephrogenesis and fibrosis among other processes. Gremlin also binds to vascular endothelial growth factor receptor-2 (VEGFR2) in endothelial cells to induce angiogenesis. In renal cells, gremlin regulates proliferation and fibrosis, but there are no data about inflammatory-related events. We have investigated the direct effects of gremlin in the kidney, evaluating whether VEGFR2 is a functional gremlin receptor. Administration of recombinant gremlin to murine kidneys induced rapid and sustained activation of VEGFR2 signalling, located in proximal tubular epithelial cells. Gremlin bound to VEGFR2 in these cells in vitro, activating this signalling pathway independently of its action as an antagonist of BMPs. In vivo, gremlin caused early renal damage, characterized by activation of the nuclear factor (NF)-B pathway linked to up-regulation of pro-inflammatory factors and infiltration of immune inflammatory cells. VEGFR2 blockade diminished gremlin-induced renal inflammatory responses. The link between gremlin/VEGFR2 and NF-B/inflammation was confirmed in vitro. Gremlin overexpression was associated with VEGFR2 activation in human renal disease and in the unilateral ureteral obstruction experimental model, where VEGFR2 kinase inhibition diminished renal inflammation. Our data show that a gremlin/VEGFR2 axis participates in renal inflammation and could be a novel target for kidney disease. Copyright (c) 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.