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      Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule

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          Abstract

          Klotho has profound effects on phosphate metabolism, but the mechanisms of how Klotho affects phosphate homeostasis is unknown. We detected Klotho in the proximal tubule cell, brush border, and urinary lumen, where phosphate homeostasis resides. Increasing Klotho in the kidney and urine chronically by transgenic overexpression or acutely by intravenous infusion caused hypophosphatemia, phosphaturia from decreased proximal phosphate reabsorption, and decreased activity and protein of the principal renal phosphate transporter NaPi-2a. The phosphaturic effect was present in FGF23-null mice, indicating a direct action distinct from Klotho's known role as a coreceptor for FGF23. Direct inhibition of NaPi-2a by Klotho was confirmed in cultured cells and in cell-free membrane vesicles characterized by acute inhibition of transport activity followed by decreased cell surface protein. Transport inhibition can be mimicked by recombinant beta-glucuronidase and is associated with proteolytic degradation and reduced surface NaPi-2a. The inhibitory effect of Klotho on NaPi-2a was blocked by beta-glucuronidase inhibitor but not by protease inhibitor. Klotho is a novel phosphaturic substance that acts as an enzyme in the proximal tubule urinary lumen by modifying glycans, which cause decreased transporter activity, followed by proteolytic degradation and possibly internalization of NaPi-2a from the apical membrane.

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          Most cited references71

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          Mutation of the mouse klotho gene leads to a syndrome resembling ageing.

          A new gene, termed klotho, has been identified that is involved in the suppression of several ageing phenotypes. A defect in klotho gene expression in the mouse results in a syndrome that resembles human ageing, including a short lifespan, infertility, arteriosclerosis, skin atrophy, osteoporosis and emphysema. The gene encodes a membrane protein that shares sequence similarity with the beta-glucosidase enzymes. The klotho gene product may function as part of a signalling pathway that regulates ageing in vivo and morbidity in age-related diseases.
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            Suppression of aging in mice by the hormone Klotho.

            A defect in Klotho gene expression in mice accelerates the degeneration of multiple age-sensitive traits. Here, we show that overexpression of Klotho in mice extends life span. Klotho protein functions as a circulating hormone that binds to a cell-surface receptor and represses intracellular signals of insulin and insulin-like growth factor 1 (IGF1), an evolutionarily conserved mechanism for extending life span. Alleviation of aging-like phenotypes in Klotho-deficient mice was observed by perturbing insulin and IGF1 signaling, suggesting that Klotho-mediated inhibition of insulin and IGF1 signaling contributes to its anti-aging properties. Klotho protein may function as an anti-aging hormone in mammals.
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              Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism

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                Author and article information

                Journal
                The FASEB Journal
                FASEB j.
                Wiley
                0892-6638
                1530-6860
                May 11 2010
                September 2010
                May 13 2010
                September 2010
                : 24
                : 9
                : 3438-3450
                Affiliations
                [1 ]Charles and Jane Pak Center of Mineral Metabolism and Clinical ResearchUniversity of Texas Southwestern Medical Center Dallas Texas USA
                [2 ]Department of Internal MedicineUniversity of Texas Southwestern Medical Center Dallas Texas USA
                [3 ]Department of PediatricsUniversity of Texas Southwestern Medical Center Dallas Texas USA
                [4 ]Department of PathologyUniversity of Texas Southwestern Medical Center Dallas Texas USA
                [5 ]Department of Developmental BiologyHarvard School of Dental Medicine Boston Massachusetts USA
                [6 ]Department of PhysiologyUniversity of Texas Southwestern Medical Center Dallas Texas USA
                Article
                10.1096/fj.10-154765
                2923354
                20466874
                2047d757-5140-460c-a6b6-c1f47db66067
                © 2010

                http://onlinelibrary.wiley.com/termsAndConditions#vor

                http://doi.wiley.com/10.1002/tdm_license_1.1

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