alpha-Klotho expression determines nitric oxide synthesis in response to FGF-23 in human aortic endothelial cells

作者：Chung, Chih-Ping; Chang, Yu-Chun; Ding, Yan; Lim, Kenneth; Liu, Qinghua; Zhu, Langjing; Zhang, Wei; Lu, Tzong-Shi; Molostvov, Guerman; Zehnder, Daniel^*; Hsiao, Li-Li^*

来源：PLos One, 2017, 12(5): e0176817.

DOI：10.1371/journal.pone.0176817

• CARDIOVASCULAR EVENTS
• VASCULAR DYSFUNCTION
• PROTECTS
• STRESS
• FGF23
• ATHEROSCLEROSIS
• RESISTANCE
• MORTALITY
• MUTATION
• DISEASES

Endothelial cells (ECs) express fibroblast growth factor (FGF) receptors and are metabolically active after treatment with FGF-23. It is not known if this effect is alpha-Klotho independent or mediated by humoral or endogenous endothelial alpha-Klotho. In the present study, we aimed to characterize EC alpha-Klotho expression within the human vascular tree and to investigate the potential role of alpha-Klotho in determining FGF-23 mediated EC regulation. Human tissue and ECs from various organs were used for immunohistochemistry and Western blot. Primary cultures of human aortic endothelial cells (HAECs) and human brain microvascular endothelial cells (HBMECs) were used to generate in vitro cell models. We found endogenous alpha-Klotho expression in ECs from various organs except in microvascular ECs from human brain. Furthermore, FGF-23 stimulated endothelial nitric oxide synthase (eNOS) expression, nitric oxide (NO) production, and cell proliferation in HAECs. Interestingly, these effects were not observed in our HBMEC model in vitro. High phosphate treatment and endothelial alpha-Klotho knockdown mitigated FGF-23 mediated eNOS induction, NO production, and cell proliferation in HAECs. Rescue treatment with soluble alpha-Klotho did not reverse endothelial FGF-23 resistance caused by reduced or absent alpha-Klotho expression in HAECs. These novel observations provide evidence for differential alpha-Klotho functional expression in the human endothelium and its presence may play a role in determining the response to FGF-23 in the vascular tree. alpha-Klotho was not detected in cerebral microvascular ECs and its absence may render these cells nonresponsive to FGF-23.

• 出版日期2017-5-2
• 单位中山大学