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      Effects of phospho- and calciotropic hormones on electrolyte transport in the proximal tubule

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          Abstract

          Calcium and phosphate are critical for a myriad of physiological and cellular processes within the organism. Consequently, plasma levels of calcium and phosphate are tightly regulated. This occurs through the combined effects of the phospho- and calciotropic hormones, parathyroid hormone (PTH), active vitamin D 3, and fibroblast growth factor 23 (FGF23). The organs central to this are the kidneys, intestine, and bone. In the kidney, the proximal tubule reabsorbs the majority of filtered calcium and phosphate, which amounts to more than 60% and 90%, respectively. The basic molecular mechanisms responsible for phosphate reclamation are well described, and emerging work is delineating the molecular identity of the paracellular shunt wherein calcium permeates the proximal tubular epithelium. Significant experimental work has delineated the molecular effects of PTH and FGF23 on these processes as well as their regulation of active vitamin D 3 synthesis in this nephron segment. The integrative effects of both phospho- and calciotropic hormones on proximal tubular solute transport and subsequently whole body calcium-phosphate balance thus have been further complicated. Here, we first review the molecular mechanisms of calcium and phosphate reabsorption from the proximal tubule and how they are influenced by the phospho- and calciotropic hormones acting on this segment and then consider the implications on both renal calcium and phosphate handling as well as whole body mineral balance.

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          Most cited references154

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          Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid.

          Maintenance of a stable internal environment within complex organisms requires specialized cells that sense changes in the extracellular concentration of specific ions (such as Ca2+). Although the molecular nature of such ion sensors is unknown, parathyroid cells possess a cell surface Ca(2+)-sensing mechanism that also recognizes trivalent and polyvalent cations (such as neomycin) and couples by changes in phosphoinositide turnover and cytosolic Ca2+ to regulation of parathyroid hormone secretion. The latter restores normocalcaemia by acting on kidney and bone. We now report the cloning of complementary DNA encoding an extracellular Ca(2+)-sensing receptor from bovine parathyroid with pharmacological and functional properties nearly identical to those of the native receptor. The novel approximately 120K receptor shares limited similarity with the metabotropic glutamate receptors and features a large extracellular domain, containing clusters of acidic amino-acid residues possibly involved in calcium binding, coupled to a seven-membrane-spanning domain like those in the G-protein-coupled receptor superfamily.
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            Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia.

            Tumor-induced osteomalacia (TIO) is one of the paraneoplastic diseases characterized by hypophosphatemia caused by renal phosphate wasting. Because removal of responsible tumors normalizes phosphate metabolism, an unidentified humoral phosphaturic factor is believed to be responsible for this syndrome. To identify the causative factor of TIO, we obtained cDNA clones that were abundantly expressed only in a tumor causing TIO and constructed tumor-specific cDNA contigs. Based on the sequence of one major contig, we cloned 2,270-bp cDNA, which turned out to encode fibroblast growth factor 23 (FGF23). Administration of recombinant FGF23 decreased serum phosphate in mice within 12 h. When Chinese hamster ovary cells stably expressing FGF23 were s.c. implanted into nude mice, hypophosphatemia with increased renal phosphate clearance was observed. In addition, a high level of serum alkaline phosphatase, low 1,25-dihydroxyvitamin D, deformity of bone, and impairment of body weight gain became evident. Histological examination showed marked increase of osteoid and widening of growth plate. Thus, continuous production of FGF23 reproduced clinical, biochemical, and histological features of TIO in vivo. Analyses for recombinant FGF23 products produced by Chinese hamster ovary cells indicated proteolytic cleavage of FGF23 at the RXXR motif. Recent genetic study indicates that missense mutations in this RXXR motif of FGF23 are responsible for autosomal dominant hypophosphatemic rickets, another hypophosphatemic disease with similar features to TIO. We conclude that overproduction of FGF23 causes TIO, whereas mutations in the FGF23 gene result in autosomal dominant hypophosphatemic rickets possibly by preventing proteolytic cleavage and enhancing biological activity of FGF23.
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              Renal control of calcium, phosphate, and magnesium homeostasis.

              Calcium, phosphate, and magnesium are multivalent cations that are important for many biologic and cellular functions. The kidneys play a central role in the homeostasis of these ions. Gastrointestinal absorption is balanced by renal excretion. When body stores of these ions decline significantly, gastrointestinal absorption, bone resorption, and renal tubular reabsorption increase to normalize their levels. Renal regulation of these ions occurs through glomerular filtration and tubular reabsorption and/or secretion and is therefore an important determinant of plasma ion concentration. Under physiologic conditions, the whole body balance of calcium, phosphate, and magnesium is maintained by fine adjustments of urinary excretion to equal the net intake. This review discusses how calcium, phosphate, and magnesium are handled by the kidneys.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Funding AcquisitionRole: Writing – Review & Editing
                Role: ConceptualizationRole: Writing – Original Draft Preparation
                Role: ConceptualizationRole: Writing – Original Draft PreparationRole: Writing – Review & Editing
                Role: ConceptualizationRole: Writing – Review & Editing
                Role: ConceptualizationRole: Writing – Review & Editing
                Journal
                F1000Res
                F1000Res
                F1000Research
                F1000Research
                F1000Research (London, UK )
                2046-1402
                3 October 2017
                2017
                : 6
                : 1797
                Affiliations
                [1 ]Department of Physiology, University of Alberta, Edmonton, Canada
                [2 ]The Women and Children’s Health Research Institute, Edmonton, Canada
                [3 ]Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
                [4 ]Department of Pediatrics, Edmonton Clinic Health Academy, University of Alberta, Edmonton, Canada
                Author notes

                Competing interests: The authors declare that they have no competing interests.

                Author information
                https://orcid.org/0000-0001-7396-7894
                Article
                10.12688/f1000research.12097.1
                5627579
                642df03d-dd99-47a1-9316-40f2dbaed723
                Copyright: © 2017 Lee JJ et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 4 October 2017
                Funding
                Funded by: the Danish Medical Research Council
                Funded by: Fabrikant Vilhelm Pedersen og Hustrus Mindelegat
                Funded by: Women and Children's Health Research Institute
                Funded by: National Sciences and Engineering Research Council of Canada
                Funded by: Canadian Institutes of Health Research
                Award ID: MOP136891
                Work in the Alexander laboratory is funded by grants from the Women and Children’s Health Research Institute, which is supported by the Stollery Children’s Hospital Foundation, the Canadian Institutes of Health Research (MOP 136891), the National Sciences and Engineering Research Council, and the Kidney Foundation of Canada. HD is supported by Fabrikant Vilhelm Pedersen og Hustrus Mindelegat, the Novo Nordisk Foundation, the Carlsberg Foundation, the A.P. Møller Foundation, the Beckett Foundation, the Lundbeck Foundation, and the Danish Medical Research Council. MRB is supported by a Vanier Canada Graduate Scholarship.
                The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Review
                Articles
                Animal Genetics
                Cell Signaling
                Endocrine & Metabolic Pharmacology
                Endocrinology
                Medical Genetics

                parathyroid hormone,fibroblast growth factor 23,phosphotropic hormomes,calciotropic hormones

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