{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T20:01:34Z","timestamp":1786132894273,"version":"build-2736575974"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","funder":[{"DOI":"10.13039\/100000738","name":"U.S. Department of VA","doi-asserted-by":"publisher","award":["BX004691 RTM"],"award-info":[{"award-number":["BX004691 RTM"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01 DK081423"],"award-info":[{"award-number":["R01 DK081423"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01 DK091392"],"award-info":[{"award-number":["R01 DK091392"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["P30 DK-079328"],"award-info":[{"award-number":["P30 DK-079328"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Jane and Charles Pak Foundation"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:sec>\n                    <jats:title>Significance Statement<\/jats:title>\n                    <jats:p>Soluble Klotho is produced in the kidney and its deficiency causes a premature aging phenotype that includes hyperphosphatemia, cardiac hypertrophy, accelerated vascular disease, endothelial dysfunction, and sarcopenia. The physiologic mechanisms that regulate soluble Klotho levels are undefined. Using molecular genetic and biochemical approaches, we show that the mouse distal convoluted tubule calcium-sensing receptor (CaSR) activates the protease A Disintegrin and Metalloproteinase 10 (ADAM10) to cleave membrane-bound Klotho, causing its shedding into the circulation in response to CaSR ligands, allosteric activators, and alkaline pH. The renal CaSR interacts with Klotho and responds to physiologic changes in pH in a manner similar to the parathyroid CaSR. The fact that the CaSR and Klotho localize in the plasma membrane and interact with ADAM10 suggests these proteins function in a complex.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      The kidney is the source of sKlotho and kidney-specific loss of Klotho leads to a phenotype resembling the premature multiorgan failure phenotype in Klotho-hypomorphic mice (\n                      <jats:italic toggle=\"yes\">kl\/kl<\/jats:italic>\n                      mice). Klotho and the Ca-sensing receptor (CaSR) are highly expressed in the distal convoluted tubule (DCT). The physiologic mechanisms that regulate sKlotho levels are unknown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We measured sKlotho in WT and tubule-specific CaSR\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      (TS-CaSR\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      ) mice treated with calcimimetics, alkali, or acid, and Klotho shed from minced mouse kidneys, and from HEK-293 cells expressing the CaSR and Klotho, in response to calcimimetics, calcilytics, alkalotic and acidic pH, and ADAM protease inhibitors. The CaSR, Klotho, and ADAM10 were imaged in mouse kidneys and cell expression systems using confocal microscopy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The CaSR, Klotho, and ADAM10 colocalize on the basolateral membrane of the DCT. Calcimimetics and HCO\n                      <jats:sub>3<\/jats:sub>\n                      increase serum sKlotho levels in WT but not in CaSR\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice, and acidic pH suppresses sKlotho levels in WT mice. In minced kidneys and cultured cells, CaSR activation with high Ca, calcimimetics, or alkali increase shed Klotho levels\n                      <jats:italic toggle=\"yes\">via<\/jats:italic>\n                      ADAM10, as demonstrated using the ADAM10 inhibitor GI254023X and siRNA. In cultured cells, the CaSR, Klotho, and ADAM10 form cell surface aggregates that disperse after CaSR activation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We identify a novel physiologic mechanism for regulation of sKlotho levels by the renal CaSR-ADAM10-Klotho pathway. We show that CaSR activators, including alkali, increase renal CaSR-stimulated Klotho shedding and predict that this mechanism is relevant to the effects of acidosis and alkali therapy on CKD progression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.2021020276","type":"journal-article","created":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T14:45:30Z","timestamp":1632321930000},"page":"3051-3065","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":16,"title":["Physiologic Regulation of Systemic Klotho Levels by Renal CaSR Signaling in Response to CaSR Ligands and pHo"],"prefix":"10.1681","volume":"32","author":[{"given":"Joonho","family":"Yoon","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas"},{"name":"Medicine Service, Veterans Affairs North Texas Health Care System, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenan","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas"},{"name":"Medicine Service, Veterans Affairs North Texas Health Care System, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunyoung","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Ferre","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanne","family":"Pastor","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianning","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orson W.","family":"Moe","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas"},{"name":"Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey N.","family":"Chang","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas"},{"name":"Medicine Service, Veterans Affairs North Texas Health Care System, Dallas, Texas"},{"name":"Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6964-7839","authenticated-orcid":false,"given":"R. Tyler","family":"Miller","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas"},{"name":"Medicine Service, Veterans Affairs North Texas Health Care System, Dallas, Texas"},{"name":"Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,12]]},"reference":[{"key":"B1-20240826","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1681\/ASN.2014101030","article-title":"Renal production, uptake, and handling of circulating \u03b1Klotho","volume":"27","author":"Hu","year":"2016","journal-title":"J Am Soc Nephrol"},{"key":"B2-20240826","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1681\/ASN.2013111209","article-title":"The kidney is the principal organ mediating klotho 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