肾
内分泌学
管周毛细血管
血管生成
内科学
生物
纺神星
纤维化
血管内皮生长因子A
血管内皮生长因子
癌症研究
医学
血管内皮生长因子受体
作者
Mingjun Shi,Jenny Maique,Ondine Cleaver,Orson W. Moe,Ming Chang Hu
标识
DOI:10.1152/ajprenal.00149.2022
摘要
The vascular endothelial growth factor (VEGF) and its cognate receptor (VEGFR2) system is crucial for cell functions associated with angiogenesis and vasculogenesis. Klotho contributes to vascular health maintenance in the kidney and other organs in mammals, but it is unknown whether renoprotection by Klotho is dependent on VEGF/VEGFR2 signaling. We used the heterozygous VEGFR2-haploinsufficient (VEGFR2+/-) mice resulting from heterozygous knock-in of green fluorescent protein (GFP) in the locus of fetal liver kinase 1 encoding VEGFR2 to test the interplay of Klotho, phosphate, and VEGFR2 in kidney function, vasculature and fibrosis. VEGFR2+/- mice displayed downregulated VEGF/VEGFR2 signaling in the kidney, lower density of peritubular capillaries, and accelerated kidney fibrosis; all of which were also found in the homozygous Klotho hypomorphic mice. High dietary phosphate induced higher plasma phosphate, greater peritubular capillary rarefaction, and more kidney fibrosis in VEGFR2+/- mice compared to wild-type (WT) mice. Genetic over-expression of Klotho significantly attenuated the elevated plasma phosphate, kidney dysfunction, peritubular capillary rarefaction, and kidney fibrosis induced by a high phosphate diet in WT mice, but only modestly ameliorated these changes in the VEGFR2+/- background. In cultured endothelial cells, VEGFR2 inhibition reduced free VEGFR2, but enhanced its co-staining of endothelial marker (CD31), and exacerbated phosphotoxicity. Klotho protein maintained VEGFR2 expression and attenuated high phosphate-induced cell injury, which was reduced by VEGFR2 inhibition. In conclusion, normal VEGFR2 function is required for vascular integrity and for Klotho to exert vascular protective and anti-fibrotic actions in the kidney partially through regulation of VEGFR2 function.
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