{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T20:00:06Z","timestamp":1786132806105,"version":"build-2736575974"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T00:00:00Z","timestamp":1764720000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["DK129241"],"award-info":[{"award-number":["DK129241"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["DK126662"],"award-info":[{"award-number":["DK126662"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000871","name":"Mayo Clinic","doi-asserted-by":"crossref","award":["FP00121925"],"award-info":[{"award-number":["FP00121925"]}],"id":[{"id":"10.13039\/100000871","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["U24DK126110"],"award-info":[{"award-number":["U24DK126110"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["DK107729"],"award-info":[{"award-number":["DK107729"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["DK126126"],"award-info":[{"award-number":["DK126126"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["DK111542"],"award-info":[{"award-number":["DK111542"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["DK100605"],"award-info":[{"award-number":["DK100605"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100023520","name":"Department of Defense Education Activity","doi-asserted-by":"crossref","award":["PR221810"],"award-info":[{"award-number":["PR221810"]}],"id":[{"id":"10.13039\/100023520","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2026,5]]},"abstract":"\n Key Points<\/jats:title>\n \n \n \n \n \u03b1<\/jats:italic>\n Klotho as an antiaging protein can extend the lifespan of healthy animals; serum\n \u03b1<\/jats:italic>\n Klotho was lower in patients with autosomal dominant polycystic kidney disease.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Transgenic\n \u03b1<\/jats:italic>\n Klotho and recombinant\n \u03b1<\/jats:italic>\n Klotho delayed cyst growth in\n Pkd1<\/jats:italic>\n mutant mouse kidneys.\n <\/jats:p>\n <\/jats:list-item>\n \n \n \u03b1<\/jats:italic>\n Klotho exerted its proapoptotic and anti-inflammatory function through interacting with and destabilizing cellular inhibitor of apoptosis protein 1.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n \n \u03b1<\/jats:italic>\n -Klotho (\n \u03b1<\/jats:italic>\n Klotho) is expressed mainly in the kidney, which is encoded by the\n KL<\/jats:italic>\n gene, existing in a membrane-bound form and a soluble circulating form. Soluble serum\n \u03b1<\/jats:italic>\n Klotho was lower in patients with autosomal dominant polycystic kidney disease (ADPKD). However, the role of\n \u03b1<\/jats:italic>\n Klotho in ADPKD remains unknown.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n To investigate the roles of\n \u03b1<\/jats:italic>\n Klotho in ADPKD, we generated transgenic\n \u03b1<\/jats:italic>\n Klotho and\n Pkd1<\/jats:italic>\n mutant\n Pkd1-HOMO-KL<\/jats:italic>\n Tg<\/jats:sup>\n mice to evaluate cyst growth and investigated underlying mechanisms with single-cell RNA sequencing analysis.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n We showed that\n \u03b1<\/jats:italic>\n Klotho was lower in diverse kidney cell types in\n Pkd1<\/jats:italic>\n mutant kidneys, which was restored by transgenic\n \u03b1<\/jats:italic>\n Klotho. We identified differential expression genes and pathways mediated by transgenic\n \u03b1<\/jats:italic>\n Klotho at single-cell resolution and determined the cytokines and their receptors mediated cell-to-cell communication networks in\n Pkd1<\/jats:italic>\n mutant and\n Pkd1-HOMO-KL<\/jats:italic>\n Tg<\/jats:sup>\n kidneys by CellChat analysis. We further showed that\n \u03b1<\/jats:italic>\n Klotho exerted a proapoptotic and anti-inflammatory function through interacting with and destabilizing cellular inhibitor of apoptosis protein 1, which disturbed TNF and its receptor mediated prosurvival complex, leading to (\n 1<\/jats:italic>\n ) the formation of predeath complex to increase cystic cell death and (\n 2<\/jats:italic>\n ) the decrease of the activation of NF-\u03baB, the expression of cytokines, and the recruitment of macrophages, resulting in a delay of cyst growth. Treatment with recombinant\n \u03b1<\/jats:italic>\n Klotho also delayed cyst growth in\n Pkd1<\/jats:italic>\n mutant kidneys.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n This study defined an unknown role and mechanism of\n \u03b1<\/jats:italic>\n Klotho in the regulation of a TNF-dependent cystic cell apoptosis and inflammation in\n Pkd1<\/jats:italic>\n mutant kidneys.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.0000000940","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T09:00:09Z","timestamp":1768208409000},"page":"928-943","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":3,"title":["\u03b1-Klotho Promotes Cell Death and Suppresses Inflammation through TNF\u2013Cellular Inhibitor of Apoptosis Protein 1 Signaling in Autosomal Dominant Polycystic Kidney Disease"],"prefix":"10.1681","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7460-0776","authenticated-orcid":false,"given":"Linda Xiaoyan","family":"Li","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota"},{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie X.","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota"},{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5928-9820","authenticated-orcid":false,"given":"James P.","family":"Calvet","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chou-Long","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Iowa, Iowa City, Iowa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8135-342X","authenticated-orcid":false,"given":"Xiaogang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota"},{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, 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