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      Vitamin K Dependent Proteins in Kidney Disease

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          Abstract

          Patients with chronic kidney disease (CKD) have an increased risk of developing vascular calcifications, as well as bone dynamics impairment, leading to a poor quality of life and increased mortality. Certain vitamin K dependent proteins (VKDPs) act mainly as calcification inhibitors, but their involvement in the onset and progression of CKD are not completely elucidated. This review is an update of the current state of knowledge about the relationship between CKD and four extrahepatic VKDPs: matrix Gla protein, osteocalcin, growth-arrest specific protein 6 and Gla-rich protein. Based on published literature in the last ten years, the purpose of this review is to address fundamental aspects about the link between CKD and circulating VKDPs levels as well as to raise new topics about how the interplay between molecular weight and charge could influence the modifications of circulating VKDPs at the glomerular level, or whether distinct renal etiologies have effect on VKDPs. This review is the output of a systematic literature search and may open future research avenues in this niche domain.

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          New insights into the biology of osteocalcin.

          Meredith L Zoch, Thomas L Clemens, Ryan C Riddle (2016)
          Osteocalcin is among the most abundant proteins in bone and is produced exclusively by osteoblasts. Initially believed to be an inhibitor of bone mineralization, recent studies suggest a broader role for osteocalcin that extends to the regulation of whole body metabolism, reproduction, and cognition. Circulating undercarboxylated osteocalcin, which is regulated by insulin, acts in a feed-forward loop to increase β-cell proliferation as well as insulin production and secretion, while skeletal muscle and adipose tissue respond to osteocalcin by increasing their sensitivity to insulin. Osteocalcin also acts in the brain to increase neurotransmitter production and in the testes to stimulate testosterone production. At least one putative receptor for osteocalcin, Gprc6a, is expressed by adipose, skeletal muscle, and the Leydig cells of the testes and appears to mediate osteocalcin's effects in these tissues. In this review, we summarize these new discoveries, which suggest that the ability of osteocalcin to function both locally in bone and as a hormone depends on a novel post-translational mechanism that alters osteocalcin's affinity for the bone matrix and bioavailability. This article is part of a Special Issue entitled Bone and diabetes.
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            Dialysis accelerates medial vascular calcification in part by triggering smooth muscle cell apoptosis.

            Rosamund McNair, Neha A Gupta, Nichola Figg … (2008)
            Vascular calcification is associated with increased morbidity and mortality in stage V chronic kidney disease, yet its early pathogenesis and initiating mechanisms in vivo remain poorly understood. To address this, we quantified the calcium (Ca) load in arteries from children (10 predialysis, 24 dialysis) and correlated it with clinical, biochemical, and vascular measures. Vessel Ca load was significantly elevated in both predialysis and dialysis and was correlated with the patients' mean serum Ca x phosphate product. However, only dialysis patients showed increased carotid intima-media thickness and increased aortic stiffness, and calcification on computed tomography was present in only the 2 patients with the highest Ca loads. Importantly, predialysis vessels appeared histologically intact, whereas dialysis vessels exhibited evidence of extensive vascular smooth muscle cell (VSMC) loss owing to apoptosis. Dialysis vessels also showed increased alkaline phosphatase activity and Runx2 and osterix expression, indicative of VSMC osteogenic transformation. Deposition of the vesicle membrane marker annexin VI and vesicle component mineralization inhibitors fetuin-A and matrix Gla-protein increased in dialysis vessels and preceded von Kossa positive overt calcification. Electron microscopy showed hydroxyapatite nanocrystals within vesicles released from damaged/dead VSMCs, indicative of their role in initiating calcification. Taken together, this study shows that Ca accumulation begins predialysis, but it is the induction of VSMC apoptosis in dialysis that is the key event in disabling VSMC defense mechanisms and leading to overt calcification, eventually with clinically detectable vascular damage. Thus the identification of factors that lead to VSMC death in dialysis will be of prime importance in preventing vascular calcification.
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              The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases.

              Cheuk-Kuen Lai, William Bruno, Simon P. Jones … (1995)
              We report the identification of ligands for Tyro 3 (alternatively called Sky, rse, brt, or tif) and Axl (alternatively, Ark or UFO), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein S, a protease regulator that is a potent anticoagulant, and Gas6, a protein related to protein S but lacking any known function. Our results are reminiscent of recent findings that the procoagulant thrombin, a protease that drives clot formation by cleaving fibrinogen to form fibrin, also binds and activates intracellular signaling via a G protein-coupled cell surface receptor. Proteases and protease regulators that also activate specific cell surface receptors may serve to integrate coagulation with associated cellular responses required for tissue repair and growth, as well as to coordinate protease cascades and associated cellular responses in other systems, such as those involved in growth and remodeling of the nervous system.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 29 March 2019
                Publication date Collection: April 2019
                Volume: 20
                Issue: 7
                Electronic Location Identifier: 1571
                Affiliations
                [1 ]Department of Molecular Sciences, University of Medicine and Pharmacy “Iuliu Hațieganu”, 400012 Cluj-Napoca, Romania; tamasilyes94@ 123456gmail.com (T.I.); vladimirpfilip@ 123456gmail.com (V.P.F.); farcasmarius47@ 123456gmail.com (M.F.); acraciun@ 123456umfcluj.ro (A.M.C.)
                [2 ]Department of Nephrology & Epidemiology and Biostatistics, Amsterdam University Medical Center, VUmc, 1117 HV Amsterdam, The Netherlands; aj.vanballegooijen@ 123456vumc.nl
                Author notes
                Author information
                https://orcid.org/0000-0003-3703-1874
                Article
                Publisher ID: ijms-20-01571
                DOI: 10.3390/ijms20071571
                PMC ID: 6479974
                PubMed ID: 30934817
                SO-VID: 8224c7e9-57b1-4972-84bd-8511f8beb946
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 20 February 2019
                Date accepted : 27 March 2019
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: vitamin k dependent proteins,matrix gla protein,osteocalcin,gas6,gla-rich protein,chronic kidney disease,calcification
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: vitamin k dependent proteins, matrix gla protein, osteocalcin, gas6, gla-rich protein, chronic kidney disease, calcification

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