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

Abstract

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 α-Klotho independent or mediated by humoral or endogenous endothelial α-Klotho. In the present study, we aimed to characterize EC α-Klotho expression within the human vascular tree and to investigate the potential role of α-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 α-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 α-Klotho knockdown mitigated FGF-23 mediated eNOS induction, NO production, and cell proliferation in HAECs. Rescue treatment with soluble α-Klotho did not reverse endothelial FGF-23 resistance caused by reduced or absent α-Klotho expression in HAECs. These novel observations provide evidence for differential α-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. α-Klotho was not detected in cerebral microvascular ECs and its absence may render these cells nonresponsive to FGF-23.

Why Should Growth Hormone (GH) Be Considered a Promising Therapeutic Agent for Arteriogenesis? Insights from the GHAS Trial

“…It is known that sKlotho increases both GH production by the anterior pituitary [172] and the local production of the hormone by the endothelium. Additionally, sKlotho inhibits the negative feedback of IGF-I on GH secretion [173]. Both molecules are essential for vascular homeostasis, as well as when this process is altered.…”

Sixteen weeks of aerobic training influence spirometry, s-klotho, and hemodynamic responses to sub-maximal exercise testing in obese men with severe obstructive sleep apnea

“…As part of the 6MWT the participant is instructed to achieve the greatest distance possible within 6minutes of walking. 26 During the test, it is important to abstain from influencing the performance of the participant in order for the results and process to be genuine and free of external affecters. 27 The overall distance achieved and the comparison to prior results influence future prognosis.…”

Why Should Growth Hormone (GH) Be Considered a Promising Therapeutic Agent for Arteriogenesis? Insights from the GHAS Trial

“…Receptors for Klotho in these tissues and the exact mechanisms of actions have not been properly stablished. It is known that circulating Klotho increases both GH production by the anterior hypophysis [195], and the local production of the hormone by the endothelium, and besides inhibits the negative feedback of IGF-I on GH secretion [196]. Both molecules are essential for vascular homeostasis, but also when this process is altered.…”