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Because the existing studies are mainly performed using heterozygous Klotho mutant (HT) mice, we focused on the effect of UUO on homozygous Klotho mutant (<jats:italic>kl\/kl<\/jats:italic>) mice. UUO kidneys from HT mice showed a significantly higher level of RTF and TGF-\u03b2\/Smad3 signaling than wild-type (WT) mice, whereas both were greatly suppressed in <jats:italic>kl\/kl<\/jats:italic> mice. Primary proximal tubular epithelial culture cells isolated from <jats:italic>kl\/kl<\/jats:italic> mice showed no suppression in TGF-\u03b21-induced epithelial mesenchymal transition (EMT) compared to those from HT mice. In the renal epithelial cell line NRK52E, a large amount of inorganic phosphate (Pi), FGF23, or calcitriol was added to the medium to mimic the <jats:italic>in vivo<\/jats:italic> homeostasis of <jats:italic>kl\/kl<\/jats:italic> mice. Neither Pi nor FGF23 antagonized TGF-\u03b21-induced EMT. In contrast, calcitriol ameliorated TGF-\u03b21-induced EMT in a dose dependent manner. A vitamin D<jats:sub>3<\/jats:sub>-deficient diet normalized the serum 1,25 (OH)<jats:sub>2<\/jats:sub> vitamin D<jats:sub>3<\/jats:sub> level in <jats:italic>kl\/kl<\/jats:italic> mice and enhanced UUO-induced RTF and TGF-\u03b2\/Smad3 signaling. In conclusion, the alleviation of UUO-induced RTF in <jats:italic>kl\/kl<\/jats:italic> mice was due to the TGF-\u03b21 signaling suppression caused by an elevated serum 1, 25(OH)<jats:sub>2<\/jats:sub> vitamin D<jats:sub>3<\/jats:sub>.<\/jats:p>","DOI":"10.1038\/srep06563","type":"journal-article","created":{"date-parts":[[2014,10,9]],"date-time":"2014-10-09T10:21:04Z","timestamp":1412850064000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Elevated serum 1,25(OH)2-vitamin D3 level attenuates renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction in kl\/kl mice"],"prefix":"10.1038","volume":"4","author":[{"given":"Yujing","family":"Sun","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gengyin","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Gui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aiko","family":"Shimokado","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masako","family":"Nakanishi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kosuke","family":"Oikawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fuyuki","family":"Sato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuteru","family":"Muragaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2014,10,9]]},"reference":[{"key":"BFsrep06563_CR1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/36285","volume":"390","author":"M Kuro-o","year":"1997","unstructured":"Kuro-o, M. et al. 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