Protective Roles of Xenotropic and Polytropic Retrovirus Receptor 1 (XPR1) in Uremic Vascular Calcification
Protective Roles of Xenotropic and Polytropic Retrovirus Receptor 1 (XPR1) in Uremic Vascular Calcification
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DOI：
10.1007/s00223-022-00947-3
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发表时间：
2022-02-02
影响因子：
4.2
通讯作者：
Kitazono, Takanari
中科院分区：
文献类型：
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作者：
Arase, Hokuto;Yamada, Shunsuke;Kitazono, Takanari
细胞磷酸转运蛋白在慢性肾脏疾病(CKD)血管钙化(VC)的发病机制中起重要作用。然而，VC与新近发现的磷酸盐输出蛋白异向性和多向性受体1(XPR1)之间的机制联系仍不清楚。我们在C57BL/6小鼠中建立了一种新的快速进展性尿毒症VC小鼠模型，并研究了XPR1的作用。手术侧肾切除与以华法林和腺嘌呤为基础的饮食相结合的8周喂养在几乎所有小鼠中诱导了广泛的主动脉腔静脉。CKD组小鼠主动脉中XPR1的表达水平早在第2周时就明显低于对照组，之后逐渐下降。饮食磷限制增加了CKD小鼠主动脉中XPR1mRNA的表达，但降低了主动脉Vc。在培养的血管平滑肌细胞(VSMCs)中，添加高磷和高钙的钙化介质不影响XPR1mRNA的表达。硫酸吲哚或骨化三醇缺乏对培养的VCMCs XPR1mRNA表达也无影响，但1-34甲状旁腺激素或成纤维细胞生长因子23可降低XPR1mRNA的表达。此外，培养的VSMCs中XPR1的缺失加剧了细胞外基质的钙化以及在钙化介质条件下的成骨表型转换。我们的数据提示，XPR1在VC的发病机制中起保护作用，其在主动脉中的减少可能参与了CKD中VC的进展。
Cellular phosphate transporters play critical roles in the pathogenesis of vascular calcification (VC) in chronic kidney disease (CKD). However, the mechanistic link between VC and xenotropic and polytropic receptor 1 (XPR1), a newly identified phosphate exporter, remains unknown. We developed a new mouse model with rapidly progressive uremic VC in C57BL/6 mice and examined the roles of XPR1. The combination of surgical heminephrectomy and 8 weeks of feeding a customized warfarin and adenine-based diet induced extensive aortic VC in almost all mice. The XPR1 mRNA level in the aorta of CKD mice was significantly lower than those in control mice as early as week 2, when there was no apparent VC, which progressively declined thereafter. Dietary phosphate restriction increased XPR1 mRNA expression in the aorta but reduced aortic VC in CKD mice. In cultured vascular smooth muscle cells (VSMCs), a calcifying medium supplemented with high phosphate and calcium did not affect XPR1 mRNA expression. The XPR1 mRNA expression in cultured VCMCs was also unaffected by administration of indoxyl sulfate or calcitriol deficiency but was decreased by 1-34 parathyroid hormone or fibroblast growth factor 23 supplementation. Furthermore, XPR1 deletion in the cultured VSMCs exacerbated calcification of the extracellular matrix as well as the osteogenic phenotypic switch under the condition of calcifying medium. Our data suggest that XPR1 plays protective roles in the pathogenesis of VC and its decrease in the aorta may contribute to the progression of VC in CKD.