Brigham and Women's Hospital, Harvard Medical School, Room 120, 41 Ave Louis Pasteur, Boston, MA 02115, USA.
Circulation. 2012 May 8;125(18):2243-55. doi: 10.1161/CIRCULATIONAHA.111.053405. Epub 2012 Apr 5.
Klotho is known to function as a cofactor for the phosphatonin, fibroblast growth factor (FGF)-23 at the kidney. FGF-23 levels rise in chronic kidney disease (CKD) despite progression of accelerated vascular calcification. There are currently conflicting data on whether FGF-23 may exhibit direct vasculoprotective effects in CKD.
In this study, we describe for the first time endogenous Klotho expression in human arteries and human aortic smooth muscle cells. We show that CKD is a state of vascular Klotho deficiency promoted by chronic circulating stress factors, including proinflammatory, uremic, and disordered metabolic conditions. Mechanistic studies demonstrated that Klotho knockdown potentiated the development of accelerated calcification through a Runx2 and myocardin-serum response factor-dependent pathway. Klotho knockdown studies further revealed that vascular cells are a Klotho-dependent target tissue for FGF-23. FGF-23 mediated cellular activation of p-ERK, p-AKT, and cellular proliferative effects, which were abrogated following Klotho knockdown. We next showed that vascular Klotho deficiency driven by procalcific stressors could be restored by vitamin D receptor activators, in vitro and further confirmed using human arterial organ cultures from CKD patients, in vivo. Furthermore, restoration of suppressed Klotho expression by vitamin D receptor activators conferred human aortic smooth muscle cells responsive to FGF-23 signaling and unmasked potential anticalcific effects.
Chronic metabolic stress factors found in CKD promote vascular Klotho deficiency. Mechanistic studies revealed a bifunctional role for local vascular Klotho, first, as an endogenous inhibitor of vascular calcification and, second, as a cofactor required for vascular FGF-23 signaling. Furthermore, vitamin D receptor activators can restore Klotho expression and unmask FGF-23 anticalcific effects.
已知 Klotho 作为肾脏中的磷酸酯酶因子，与成纤维细胞生长因子 23（FGF-23）共同发挥作用。尽管血管钙化加速进展，慢性肾脏病（CKD）患者的 FGF-23 水平仍会升高。目前对于 FGF-23 是否可能在 CKD 中表现出直接的血管保护作用，存在相互矛盾的数据。
本研究首次描述了人动脉和人主动脉平滑肌细胞中内源性 Klotho 的表达。我们发现 CKD 是一种血管 Klotho 缺乏的状态，这种缺乏是由慢性循环应激因素引起的，包括炎症、尿毒症和代谢紊乱等。机制研究表明，Klotho 敲低通过 Runx2 和心肌细胞反应因子依赖的途径增强了加速钙化的发展。Klotho 敲低研究进一步表明，血管细胞是 FGF-23 的依赖 Klotho 的靶组织。FGF-23 通过 p-ERK、p-AKT 的细胞激活和细胞增殖作用，Klotho 敲低后这些作用被阻断。我们接下来表明，由促钙化应激因子驱动的血管 Klotho 缺乏可以通过维生素 D 受体激动剂在体外恢复，并在体内进一步通过 CKD 患者的人动脉器官培养物证实。此外，维生素 D 受体激动剂恢复受抑制的 Klotho 表达赋予了人主动脉平滑肌细胞对 FGF-23 信号的反应能力，并揭示了潜在的抗钙化作用。
在 CKD 中发现的慢性代谢应激因子促进血管 Klotho 缺乏。机制研究揭示了局部血管 Klotho 的双重功能，首先，作为血管钙化的内源性抑制剂，其次，作为血管 FGF-23 信号的辅助因子。此外，维生素 D 受体激动剂可以恢复 Klotho 的表达并揭示 FGF-23 的抗钙化作用。
