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Klotho modulates FGF23-mediated NO synthesis and oxidative stress in human coronary artery endothelial cells

  • Signaling and cell physiology
  • Published:
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Abstract

Chronic kidney disease (CKD) is a state of Klotho deficiency and excess of the phosphaturic hormone fibroblast growth factor 23 (FGF23). Both dysregulations were shown to be associated with endothelial dysfunction in humans, but direct vascular effects of FGF23 remain largely elusive. In vitro experiments were performed to assess the effects of FGF23 (10 ng/mL) in relation to its co-receptor Klotho on nitric oxide (NO) synthesis and reactive oxygen species (ROS) formation and detoxification in human coronary artery endothelial cells (HCAEC). Membrane-bound Klotho is expressed in HCAEC, and FGF23 increases the expression of the Klotho shedding protease ADAM17, and consequently the secretion of soluble Klotho. FGF23 activates FGF receptor 1 and stimulates NO release via Akt-dependent activation of endothelial NO synthase (eNOS). Both FGF receptor (FGFR)-dependent ROS formation via activation of NADPH oxidase 2 (Nox2) as well as ROS degradation via superoxide dismutase 2 (SOD2) and catalase (CAT) is stimulated by FGF23. Pre-incubation with a Klotho inhibitor blunts the FGF23-stimulated Akt-eNOS activation and NO synthesis, and decreases ROS degradation by blocking SOD2 and CAT enzymes, whereas FGF23-stimulated ROS synthesis via Nox2 is unaffected, resulting in low NO bioavailability and increased oxidative stress. Our data indicate that in the presence of Klotho, FGF23 induces NO release in HCAEC and its stimulating effects on ROS production are counterbalanced by increased ROS degradation. In states of Klotho deficiency, e.g., CKD, FGF23-mediated NO synthesis is blunted and ROS formation overrules ROS degradation. Thus, FGF23 excess may primarily promote oxidative stress and thus endothelial dysfunction.

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Acknowledgments

The authors have no conflict of interest to declare regarding this paper. No external funding was received for this study. The authors thank Prof. Dr. Michael Klintschar (Institute for Forensic Medicine, Hannover Medical School, Germany) and Prof. Dr. Ruthild Weber (Department of Human Genetics, Hannover Medical School, Germany) for collection of tissue samples from the human heart, aorta, and kidney. Furthermore, they would like to thank Dr. Benjamin Förthmann (Institute of Neuroanatomy, Hannover Medical School, Germany) for HEK-293T cells and Anja Ziolek for their excellent technical assistance.

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  1. Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    Beatrice Richter, Jacqueline Haller, Dieter Haffner & Maren Leifheit-Nestler

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Richter, B., Haller, J., Haffner, D. et al. Klotho modulates FGF23-mediated NO synthesis and oxidative stress in human coronary artery endothelial cells. Pflugers Arch - Eur J Physiol 468, 1621–1635 (2016). https://doi.org/10.1007/s00424-016-1858-x

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