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Abstract：
Chronic kidney disease (CKD) is linked to greater prevalence and rapid progression of calcific aortic valve disease (CAVD) characterized by valvular leaflet fibrosis and calcification. Fibroblast growth factor 23 (FGF23) level is elevated, and anti-aging protein Klotho is reduced in CKD patients. However, the roles of FGF23 and Klotho in the mechanism of aortic valve fibrosis and calcification remain unclear. We hypothesized that FGF23 mediates CKD-induced CAVD by enhancing aortic valve interstitial cell (AVIC) fibrosis and calcification, while soluble Klotho inhibits FGF23 effect. Methods and Results: In an old mouse model of CKD, kidney damages were accompanied by aortic valve thickening and calcification. FGF23 levels in plasma and aortic valve were increased, while Klotho levels were decreased. Recombinant FGF23 elevated the inflammatory, fibrogenic, and osteogenic activities in AVICs. Neutralizing antibody or shRNA targeting FGF23 suppressed the pathobiological activities in AVICs from valves affected by CAVD. FGF23 exerts its effects on AVICs via FGF receptor (FGFR)/Yes-associated protein (YAP) signaling, and inhibition of FGFR/YAP reduced FGF23\'s potency in AVICs. Recombinant Klotho downregulated the pathobiological activities in AVICs exposed to FGF23. Incubation of FGF23 with Klotho formed complexes and decreased FGF23\'s potency. Further, treatment of CKD mice with recombinant Klotho attenuated aortic valve lesions. Conclusion: This study demonstrates that CKD induces FGF23 accumulation, Klotho insufficiency and aortic valve lesions in old mice. FGF23 upregulates the inflammatory, fibrogenic and osteogenic activities in AVICs via the FGFR/YAP signaling pathway. Soluble Klotho suppresses FGF23 effect through molecular interaction and is capable of mitigating CKD-induced CAVD.
摘要：
慢性肾脏疾病（CKD）与以瓣膜小叶纤维化和钙化为特征的钙化性主动脉瓣疾病（CAVD）的患病率更高，进展迅速。成纤维细胞生长因子23（FGF23）水平升高，CKD患者抗衰老蛋白Klotho降低。然而,FGF23和Klotho在主动脉瓣纤维化和钙化机制中的作用尚不清楚.我们假设FGF23通过增强主动脉瓣间质细胞（AVIC）纤维化和钙化来介导CKD诱导的CAVD，而可溶性Klotho抑制FGF23效应。方法和结果：在一个古老的CKD小鼠模型中，肾脏损害伴有主动脉瓣增厚和钙化。血浆和主动脉瓣中的FGF23水平升高，而Klotho水平下降。重组FGF23提高了炎症，纤维化，和AVICs中的成骨活性。靶向FGF23的中和抗体或shRNA抑制了受CAVD影响的瓣膜的AVIC中的病理生物学活性。FGF23通过FGF受体（FGFR）/Yes相关蛋白（YAP）信号发挥其对AVIC的作用，FGFR/YAP的抑制降低了FGF23在AVIC中的效力。重组Klotho下调了暴露于FGF23的AVIC中的病理生物学活性。将FGF23与Klotho一起孵育形成复合物并降低FGF23的效力。Further,用重组Klotho治疗CKD小鼠减轻主动脉瓣病变。结论：这项研究表明，CKD诱导FGF23的积累，老年小鼠的Klotho功能不全和主动脉瓣病变。FGF23上调炎症，通过FGFR/YAP信号通路在AVIC中的纤维化和成骨活性。可溶性Klotho通过分子相互作用抑制FGF23效应，并能够减轻CKD诱导的CAVD。
