15
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Related collections

          Most cited references25

          • Record: found
          • Abstract: found
          • Article: not found

          The kidney is the principal organ mediating klotho effects.

          Klotho was discovered as an antiaging gene, and α-Klotho (Klotho) is expressed in multiple tissues with a broad set of biologic functions. Membrane-bound Klotho binds fibroblast growth factor 23 (FGF23), but a soluble form of Klotho is also produced by alternative splicing or cleavage of the extracellular domain of the membrane-bound protein. The relative organ-specific contributions to the levels and effects of circulating Klotho remain unknown. We explored these issues by generating a novel mouse strain with Klotho deleted throughout the nephron (Six2-KL(-/-)). Klotho shedding from Six2-KL(-/-) kidney explants was undetectable and the serum Klotho level was reduced by approximately 80% in Six2-KL(-/-) mice compared with wild-type littermates. Six2-KL(-/-) mice exhibited severe growth retardation, kyphosis, and premature death, closely resembling the phenotype of systemic Klotho knockout mice. Notable biochemical changes included hyperphosphatemia, hypercalcemia, hyperaldosteronism, and elevated levels of 1,25-dihydroxyvitamin D and Fgf23, consistent with disrupted renal Fgf23 signaling. Kidney histology demonstrated interstitial fibrosis and nephrocalcinosis in addition to absent dimorphic tubules. A direct comparative analysis between Six2-KL(-/-) and systemic Klotho knockout mice supports extensive, yet indistinguishable, extrarenal organ manifestations. Thus, our data reveal the kidney as the principal contributor of circulating Klotho and Klotho-induced antiaging traits. Copyright © 2014 by the American Society of Nephrology.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Electrical resistance of brain microvascular endothelium.

            A newly developed technique for determination of the electrical resistance of the capillary wall was applied to microvessels at the surface of the frog brain. Current was injected into a capillary or venule via a microelectrode and the ensuing intravascular potential profile away from the current source was determined with a second microelectrode placed at various positions along the capillary. The membrane resistance was calculated according to the theory for leaky cables used in determinations of axon membrane resistance. The average resistance was 1870 omega . cm2. Since the surface vessels of the frog brain are devoid of glial investment but otherwise similar to brain parenchymal vessels, the results prove that the endothelium is the site of the blood-brain barrier. The electrical resistance is similar to that of a 'tight' epithelium.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Klotho suppresses RIG-I-mediated senescence-associated inflammation.

              It is well known that aged or senescent cells develop a complex senescence-associated secretory phenotype (SASP), which is observed both in culture and in vivo. However, the mechanisms underlying the induction of the SASP are largely unknown. We demonstrate that retinoic-acid-inducible gene-I (RIG-I) is induced through the ataxia telangiectasia mutated-interferon regulatory factor 1 (ATM-IRF1) axis in senescent cells and that RIG-I signalling mediates the expression of two important mediators of inflammation, interleukin-6 (IL-6) and IL-8. Klotho has been associated with ageing. We show here that the intracellular, but not the secreted, form of klotho interacts with RIG-I and that this interaction inhibits RIG-I-induced expression of IL-6 and IL-8 both in vitro and in vivo. Our study uncovers a mechanism in which klotho functions as an anti-ageing factor through the suppression of RIG-I-mediated inflammation. © 2011 Macmillan Publishers Limited. All rights reserved.
                Bookmark

                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                2 May 2017
                2017
                : 12
                : 5
                : e0176817
                Affiliations
                [1 ]Department of Neurology, Neurological Institute, Taipei Veterans general Hospital and National Yang Ming University, Taipei, Taiwan
                [2 ]Department of Medicine, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America
                [3 ]Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Key Laboratory of Nephrology, Ministry of Health, Guangzhou, Guangdong, China
                [4 ]Department of Nephrology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
                [5 ]Department of Gastroenterology, Guizhou Cancer Hospital of Guizhou Medical University, Guiyang, Guizhou, China
                [6 ]North Cumbria University Hospital NHS Trust, Carlisle, Cumbria, United Kingdom
                Hungarian Academy of Sciences, HUNGARY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: LLH.

                • Data curation: CPC LLH.

                • Formal analysis: CPC YCC.

                • Funding acquisition: LLH.

                • Investigation: CPC YCC YD KL QL LZ WZ TSL DZ.

                • Methodology: CPC DZ.

                • Resources: LLH GM DZ.

                • Supervision: LLH.

                • Validation: CPC YCC YD.

                • Visualization: CPC YCC YD.

                • Writing – original draft: CPC.

                • Writing – review & editing: CPC YCC YD KL DZ LLH.

                ‡ These authors are co-first authors on this work.

                Article
                PONE-D-16-26467
                10.1371/journal.pone.0176817
                5413063
                28463984
                7ba1ea03-a477-446f-89df-24fccc689826
                © 2017 Chung et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 1 July 2016
                : 18 April 2017
                Page count
                Figures: 4, Tables: 0, Pages: 15
                Funding
                This work was supported by SDSC Global Foundation, and Dr. Qinghua Liu, one of the co-authors, was supported by grants from National Natural Science Foundation of China (No.81370863).
                Categories
                Research Article
                Medicine and Health Sciences
                Endocrinology
                Endocrine Physiology
                Growth Factors
                Fibroblast Growth Factor
                Biology and Life Sciences
                Physiology
                Endocrine Physiology
                Growth Factors
                Fibroblast Growth Factor
                Medicine and Health Sciences
                Physiology
                Endocrine Physiology
                Growth Factors
                Fibroblast Growth Factor
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Epithelial Cells
                Endothelial Cells
                Biology and Life Sciences
                Anatomy
                Biological Tissue
                Epithelium
                Epithelial Cells
                Endothelial Cells
                Medicine and Health Sciences
                Anatomy
                Biological Tissue
                Epithelium
                Epithelial Cells
                Endothelial Cells
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Molecular Biology Assays and Analysis Techniques
                Gene Expression and Vector Techniques
                Protein Expression
                Research and Analysis Methods
                Molecular Biology Techniques
                Molecular Biology Assays and Analysis Techniques
                Gene Expression and Vector Techniques
                Protein Expression
                Physical Sciences
                Chemistry
                Chemical Compounds
                Phosphates
                Biology and Life Sciences
                Biochemistry
                Neurochemistry
                Neurochemicals
                Nitric Oxide
                Biology and Life Sciences
                Neuroscience
                Neurochemistry
                Neurochemicals
                Nitric Oxide
                Biology and life sciences
                Genetics
                Gene expression
                Gene regulation
                Small interfering RNAs
                Biology and life sciences
                Biochemistry
                Nucleic acids
                RNA
                Non-coding RNA
                Small interfering RNAs
                Biology and Life Sciences
                Anatomy
                Cardiovascular Anatomy
                Endothelium
                Medicine and Health Sciences
                Anatomy
                Cardiovascular Anatomy
                Endothelium
                Research and Analysis Methods
                Experimental Organism Systems
                Model Organisms
                Mouse Models
                Research and Analysis Methods
                Model Organisms
                Mouse Models
                Research and Analysis Methods
                Experimental Organism Systems
                Animal Models
                Mouse Models
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

                Uncategorized
                Uncategorized

                Comments

                Comment on this article