VEGF regulates local inhibitory complement proteins in the eye and kidney.
VEGF regulates local inhibitory complement proteins in the eye and kidney.
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DOI：
10.1172/jci86418
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发表时间：
2017-01-03
期刊：
影响因子：
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通讯作者：
Friedlander M
中科院分区：
文献类型：
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作者：
Keir LS;Firth R;Aponik L;Feitelberg D;Sakimoto S;Aguilar E;Welsh GI;Richards A;Usui Y;Satchell SC;Kuzmuk V;Coward RJ;Goult J;Bull KR;Sharma R;Bharti K;Westenskow PD;Michael IP;Saleem MA;Friedlander M
外部视网膜和肾小球功能依赖于由VEGF维持的专门的脉管系统，所述VEGF分别由相邻的上皮细胞、视网膜色素上皮（RPE）和足细胞产生。RPE和足细胞源性VEGF的失调与湿性年龄相关性黄斑变性（ARMD）、脉络膜毛细血管变性和肾小球血栓性微血管病（TMA）中的新血管形成相关。由于补体激活和抑制性补体因子H（CFH）的遗传变异也是ARMD和TMA的特征，我们假设VEGF和CFH相互作用。在这里，我们证明了VEGF抑制通过减少VEGFR 2/PKC-α/CREB信号传导减少眼睛和肾脏中的局部CFH和其他补体调节因子。携带疾病相关CFH遗传变异的患者足细胞和RPE细胞比对照组有更多的替代补体途径沉积。这些沉积物通过VEGF拮抗作用（一种常见的湿ARMD治疗）增加，表明VEGF抑制可降低细胞补体调节能力。VEGF拮抗作用还增加了内皮细胞活化的标志物，而遗传补体抑制作用部分减少了内皮细胞活化的标志物。总之，这些结果表明，VEGF保护视网膜和肾小球微血管，不仅通过VEGFR 2介导的血管营养作用，而且还通过调节局部补体蛋白，可以防止补体介导的损伤。虽然需要进一步研究，但这些发现可能与接受VEGF拮抗剂的患者相关。
Outer retinal and renal glomerular functions rely on specialized vasculature maintained by VEGF that is produced by neighboring epithelial cells, the retinal pigment epithelium (RPE) and podocytes, respectively. Dysregulation of RPE- and podocyte-derived VEGF is associated with neovascularization in wet age-related macular degeneration (ARMD), choriocapillaris degeneration, and glomerular thrombotic microangiopathy (TMA). Since complement activation and genetic variants in inhibitory complement factor H (CFH) are also features of both ARMD and TMA, we hypothesized that VEGF and CFH interact. Here, we demonstrated that VEGF inhibition decreases local CFH and other complement regulators in the eye and kidney through reduced VEGFR2/PKC-α/CREB signaling. Patient podocytes and RPE cells carrying disease-associated CFH genetic variants had more alternative complement pathway deposits than controls. These deposits were increased by VEGF antagonism, a common wet ARMD treatment, suggesting that VEGF inhibition could reduce cellular complement regulatory capacity. VEGF antagonism also increased markers of endothelial cell activation, which was partially reduced by genetic complement inhibition. Together, these results suggest that VEGF protects the retinal and glomerular microvasculature, not only through VEGFR2-mediated vasculotrophism, but also through modulation of local complement proteins that could protect against complement-mediated damage. Though further study is warranted, these findings could be relevant for patients receiving VEGF antagonists.