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      α-Klotho Expression in Human Tissues.

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          Abstract

          α-Klotho has emerged as a powerful regulator of the aging process. To date, the expression profile of α-Klotho in human tissues is unknown, and its existence in some human tissue types is subject to much controversy.

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          Klotho deficiency causes vascular calcification in chronic kidney disease.

          Ming Hu, Mingjun Shi, Jianning Zhang … (2011)
          Soft-tissue calcification is a prominent feature in both chronic kidney disease (CKD) and experimental Klotho deficiency, but whether Klotho deficiency is responsible for the calcification in CKD is unknown. Here, wild-type mice with CKD had very low renal, plasma, and urinary levels of Klotho. In humans, we observed a graded reduction in urinary Klotho starting at an early stage of CKD and progressing with loss of renal function. Despite induction of CKD, transgenic mice that overexpressed Klotho had preserved levels of Klotho, enhanced phosphaturia, better renal function, and much less calcification compared with wild-type mice with CKD. Conversely, Klotho-haploinsufficient mice with CKD had undetectable levels of Klotho, worse renal function, and severe calcification. The beneficial effect of Klotho on vascular calcification was a result of more than its effect on renal function and phosphatemia, suggesting a direct effect of Klotho on the vasculature. In vitro, Klotho suppressed Na(+)-dependent uptake of phosphate and mineralization induced by high phosphate and preserved differentiation in vascular smooth muscle cells. In summary, Klotho is an early biomarker for CKD, and Klotho deficiency contributes to soft-tissue calcification in CKD. Klotho ameliorates vascular calcification by enhancing phosphaturia, preserving glomerular filtration, and directly inhibiting phosphate uptake by vascular smooth muscle. Replacement of Klotho may have therapeutic potential for CKD.
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            Augmented Wnt signaling in a mammalian model of accelerated aging.

            Hongjun Liu, Maria Fergusson, Rogerio M. Castilho … (2007)
            The contribution of stem and progenitor cell dysfunction and depletion in normal aging remains incompletely understood. We explored this concept in the Klotho mouse model of accelerated aging. Analysis of various tissues and organs from young Klotho mice revealed a decrease in stem cell number and an increase in progenitor cell senescence. Because klotho is a secreted protein, we postulated that klotho might interact with other soluble mediators of stem cells. We found that klotho bound to various Wnt family members. In a cell culture model, the Wnt-klotho interaction resulted in the suppression of Wnt biological activity. Tissues and organs from klotho-deficient animals showed evidence of increased Wnt signaling, and ectopic expression of klotho antagonized the activity of endogenous and exogenous Wnt. Both in vitro and in vivo, continuous Wnt exposure triggered accelerated cellular senescence. Thus, klotho appears to be a secreted Wnt antagonist and Wnt proteins have an unexpected role in mammalian aging.
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              Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule.

              Ming Hu, Mingjun Shi, Jianning Zhang … (2010)
              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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                Author and article information

                Journal
                Journal ID (iso-abbrev): J. Clin. Endocrinol. Metab.
                Title: The Journal of clinical endocrinology and metabolism
                Publisher: The Endocrine Society
                ISSN (Electronic): 1945-7197
                ISSN (Print): 0021-972X
                Publication date (Electronic): Oct 2015
                Volume: 100
                Issue: 10
                Affiliations
                [1 ] Renal Division (K.L., T.L., L.-L.H.), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Cambridge Centre for Proteomics (A.G., K.S.L., T.F.H.), and School of Clinical Medicine (I.B.W., T.F.H.), University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Department of Pathology (D.S., S.J., S.T.), University Hospitals Coventry and Warwickshire, NHS Trust, Coventry CV2 2DX, United Kingdom; and Division of Translational Research (G.M., D.Z.), Warwick Medical School, University of Warwick, Coventry CV2 2DX, United Kingdom.
                Article
                DOI: 10.1210/jc.2015-1800
                PMC ID: 4596032
                PubMed ID: 26280509
                SO-VID: 5dc717e0-013e-46ed-8da0-e04bd5f1a2a5
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