{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:51:03Z","timestamp":1791175863632,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:00:00Z","timestamp":1791072000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:00:00Z","timestamp":1791072000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23K07680"],"award-info":[{"award-number":["23K07680"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["26K11205"],"award-info":[{"award-number":["26K11205"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["15H05788"],"award-info":[{"award-number":["15H05788"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008667","name":"SENSHIN Medical Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008667","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007263","name":"Astellas Foundation for Research on Metabolic Disorders","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007263","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007428","name":"Naito Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100032149","name":"Harmonic Ito Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100032149","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Physiologica"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>Hyperkalemia is prevalent in the elderly, and underlying molecular mechanisms remain incompletely understood. We hypothesized that Klotho deficiency, a feature of aging, impairs renal potassium homeostasis and contributes to hyperkalemia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Klotho heterozygous knockout (KLhet) mice, characterized by reduced Klotho levels, were used to investigate determinants of potassium handling, including renal outer medullary potassium channel (ROMK)1, the epithelial sodium channel (ENaC), which provides the driving force for ROMK\u2010mediated potassium secretion, and plasma aldosterone concentration (PAC).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      KLhet mice developed hyperkalemia with reduced urinary potassium excretion, accompanied by activation of renal mechanistic target of rapamycin complex 1 (mTORC1) signaling, indicated by increased phosphorylated S6, and decreased ROMK1 abundance in the plasma membrane fraction. Adrenal expression of aldosterone synthase\n                      <jats:italic>Cyp11b2<\/jats:italic>\n                      and PAC were elevated, and ENaC activity was enhanced, as evidenced by increased cleavage of \u03b1\u2010 and \u03b3\u2010ENaC subunits, partially compensating for impaired potassium excretion. Pharmacological ENaC inhibition with amiloride precipitated severe hyperkalemia in KLhet mice. In contrast, treatment with the mTORC1 inhibitor rapamycin or Klotho supplementation suppressed renal mTORC1 signaling, restored plasma membrane ROMK1 abundance, increased urinary potassium excretion, and normalized serum potassium levels, with reduced\n                      <jats:italic>Cyp11b2<\/jats:italic>\n                      expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Klotho deficiency impairs renal potassium handling through mTORC1\u2010dependent downregulation of ROMK, with compensatory hyperaldosteronism and ENaC activation. These findings highlight an important role of the Klotho\u2013mTORC1 axis in distal potassium homeostasis and its potential as a therapeutic target for Klotho deficiency\u2013associated hyperkalemia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/apha.70325","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T03:56:51Z","timestamp":1791172611000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Klotho Deficiency Impairs Distal Potassium Homeostasis Through\n                    <scp>mTORC1<\/scp>\n                    \u2010Dependent Suppression of\n                    <scp>ROMK<\/scp>"],"prefix":"10.1111","volume":"242","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1332-8537","authenticated-orcid":false,"given":"Wakako","family":"Kawarazaki","sequence":"first","affiliation":[{"name":"Center for Basic Medical Research International University of Health and Welfare (IUHW)  Narita Chiba Japan"},{"name":"Department of Pharmacology, School of Medicine IUHW  Narita Chiba Japan"},{"name":"Department of Molecular Biology, School of Medicine IUHW  Narita Chiba Japan"},{"name":"Division of Clinical Epigenetics, Research Center for Advanced Science and Technology The University of Tokyo  Meguro Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhiro","family":"Ayuzawa","sequence":"additional","affiliation":[{"name":"Division of Clinical Epigenetics, Research Center for Advanced Science and Technology The University of Tokyo  Meguro Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9542-847X","authenticated-orcid":false,"given":"Mitsuhiro","family":"Nishimoto","sequence":"additional","affiliation":[{"name":"Division of Clinical Epigenetics, Research Center for Advanced Science and Technology The University of Tokyo  Meguro Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1885-1263","authenticated-orcid":false,"given":"Daigoro","family":"Hirohama","sequence":"additional","affiliation":[{"name":"Division of Clinical Epigenetics, Research Center for Advanced Science and Technology The University of Tokyo  Meguro Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9411-1611","authenticated-orcid":false,"given":"Kohei","family":"Ueda","sequence":"additional","affiliation":[{"name":"Division of Clinical Epigenetics, Research Center for Advanced Science and Technology The University of Tokyo  Meguro Tokyo Japan"},{"name":"Department of Physiology, School of Medicine IUHW  Narita Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1650-1734","authenticated-orcid":false,"given":"Takeshi","family":"Marumo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine IUHW  Narita Chiba Japan"},{"name":"Department of Molecular Biology, School of Medicine IUHW  Narita Chiba Japan"},{"name":"Division of Clinical Epigenetics, Research Center for Advanced Science and Technology The University of Tokyo  Meguro Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9141-7060","authenticated-orcid":false,"given":"Toshiro","family":"Fujita","sequence":"additional","affiliation":[{"name":"Division of Clinical Epigenetics, Research Center for Advanced Science and Technology The University of Tokyo  Meguro Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,4]]},"reference":[{"issue":"5","key":"e_1_2_11_2_1","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1016\/j.ekir.2021.02.038","article-title":"Hyperkalemia and Its Association With Mortality, Cardiovascular Events, Hospitalizations, and Intensive Care Unit Admissions in a Population\u2010Based Retrospective Cohort","volume":"6","author":"Hougen I.","year":"2021","journal-title":"Kidney International Reports"},{"issue":"6","key":"e_1_2_11_3_1","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1080\/03007995.2018.1433141","article-title":"The Prevalence of Hyperkalemia in the United States","volume":"34","author":"Betts K. 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