Protease-activated receptor 2 protects against VEGF inhibitor-induced glomerular endothelial and podocyte injury
Protease-activated receptor 2 protects against VEGF inhibitor-induced glomerular endothelial and podocyte injury
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蛋白酶激活受体 2 可防止 VEGF 抑制剂诱导的肾小球内皮和足细胞损伤
DOI：
10.1038/s41598-019-39914-8
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发表时间：
2019
影响因子：
4.6
通讯作者：
Takahashi Nobuyuki
中科院分区：
文献类型：
--
作者：
Oe Yuji;Fushima Tomofumi;Sato Emiko;Sekimoto Akiyo;Kisu Kiyomi;Sato Hiroshi;Sugawara Junichi;Ito Sadayoshi;Takahashi Nobuyuki
血管内皮生长因子(VEGF)抑制剂会导致肾小球损伤。我们最近发现，由Xa因子激活的蛋白水解酶激活受体2(PAR2)可加重糖尿病肾病。然而，PAR2在血管内皮细胞生长因子阻断所致肾小球损伤中的作用尚不清楚。在此，我们研究了PAR2缺失在血管内皮生长因子抑制剂诱导的肾小球损伤中的作用。虽然单独给予抗血管内皮生长因子抗体在野生型小鼠中没有表现出肾脏表型，但对缺乏内皮型一氧化氮合酶(ENOS)的小鼠给予该抗体会导致肾小球损伤。与我们预期的不同，在缺乏PAR2和eNOS的小鼠中应用抗血管内皮生长因子抗体加剧了蛋白尿，并降低了肾脏CD31、促血管生成的血管内皮生长因子和血管生成相关趋化因子的表达水平。在这个缺乏PAR2的小鼠模型中，足细胞损伤也很明显。我们的结果提示PAR2对血管内皮生长因子抑制剂诱导的肾小球内皮细胞和足细胞损伤具有保护作用。
Vascular endothelial growth factor (VEGF) inhibitors cause glomerular injury. We have recently shown that activation of protease-activated receptor 2 (PAR2) by factor Xa exacerbated diabetic kidney disease. However, the role of PAR2 in glomerular injury induced by VEGF blockade is not known. Herein, we investigated the effect of the lack of PAR2 on VEGF inhibitor-induced glomerular injury. Although administering an anti-VEGF antibody by itself did not show renal phenotype in wild type mice, its administration to mice lacking endothelial nitric oxide synthase (eNOS) caused glomerular injury. Different from what we expected, administration of an anti-VEGF antibody in mice lacking PAR2 and eNOS exacerbated albuminuria and reduced the expression levels of CD31, pro-angiogenic VEGF, and angiogenesis-related chemokines in their kidneys. Podocyte injury was also evident in this model of mice lacking PAR2. Our results suggest that PAR2 is protective against VEGF inhibitor-induced glomerular endothelial and podocyte injury.