{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T04:11:30Z","timestamp":1791000690500,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2018,10,16]],"date-time":"2018-10-16T00:00:00Z","timestamp":1539648000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["16K3457190"],"award-info":[{"award-number":["16K3457190"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Physiologica"],"published-print":{"date-parts":[[2019,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Klotho interacts with various membrane proteins, such as receptors for transforming growth factor (TGF)\u2010\u03b2 and insulin\u2010like growth factor (IGF), to alter their function. Renal expression of klotho is diminished in diabetes. The present study examined whether exogenous klotho protein supplementation ameliorates kidney injury and renin\u2013angiotensin system (RAS) in db\/db mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We investigated the effects of klotho supplementation on diabetic kidney injury and RAS. Recombinant human klotho protein (10\u00a0\u03bcg\/kg\/d) was administered to db\/db mice daily.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Klotho protein supplementation reduced kidney weight, systolic blood pressure (SBP), albuminuria, glomerular filtration rate, and 8\u2010epi\u2010prostaglandin F2\u03b1 excretion without affecting body weight. Although klotho supplementation did not alter glycated albumin, it reduced renal angiotensin II levels associated with reduced renal expression of angiotensinogen. Klotho supplementation improved renal expression of superoxide dismutase (SOD), and endogenous renal expression of klotho. Klotho supplementation reduced the levels of hypoxia\u2010inducible factor, phosphorylated Akt, and phosphorylated mTOR and decreased the renal expression of TGF\u2010\u03b2, tumour necrosis factor (TNF), and fibronectin.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These data indicate that klotho supplementation reduces blood pressure and albuminuria along with ameliorating renal RAS activation in db\/db mice. Furthermore, these results suggest that klotho inhibits IGF signalling, induces SOD expression to reduce oxidative stress, and suppresses Akt\u2010mTOR signalling to inhibit abnormal kidney growth. Collectively, the results suggest that klotho inhibits TGF\u2010\u03b2 and TNF signalling, resulting in a decline in renal fibrosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/apha.13190","type":"journal-article","created":{"date-parts":[[2018,9,25]],"date-time":"2018-09-25T05:10:17Z","timestamp":1537852217000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":69,"title":["Klotho protein supplementation reduces blood pressure and renal hypertrophy in db\/db mice, a model of type 2 diabetes"],"prefix":"10.1111","volume":"225","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3383-1340","authenticated-orcid":false,"given":"Tsuneo","family":"Takenaka","sequence":"first","affiliation":[{"name":"International University of Health and Welfare Minato Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Kobori","sequence":"additional","affiliation":[{"name":"International University of Health and Welfare Minato Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Miyazaki","sequence":"additional","affiliation":[{"name":"Saitama Medical University Moroyama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromichi","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Saitama Medical University Moroyama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Nishiyama","sequence":"additional","affiliation":[{"name":"Kagawa University Takamatsu Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naohito","family":"Ishii","sequence":"additional","affiliation":[{"name":"Kitasato University Sagamihara Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maho","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Keio University Shinjuku 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