title: Elevated serum 1,25(OH)2-vitamin D3 level attenuates renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction in kl/kl mice.
abstract: Previous studies have suggested that Klotho provides reno-protection against unilateral ureteral obstruction (UUO)-induced renal tubulointerstitial fibrosis (RTF). Because the existing studies are mainly performed using heterozygous Klotho mutant (HT) mice, we focused on the effect of UUO on homozygous Klotho mutant (kl/kl) mice. UUO kidneys from HT mice showed a significantly higher level of RTF and TGF-β/Smad3 signaling than wild-type (WT) mice, whereas both were greatly suppressed in kl/kl mice. Primary proximal tubular epithelial culture cells isolated from kl/kl mice showed no suppression in TGF-β1-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 in vivo homeostasis of kl/kl mice. Neither Pi nor FGF23 antagonized TGF-β1-induced EMT. In contrast, calcitriol ameliorated TGF-β1-induced EMT in a dose dependent manner. A vitamin D3-deficient diet normalized the serum 1,25 (OH)2 vitamin D3 level in kl/kl mice and enhanced UUO-induced RTF and TGF-β/Smad3 signaling. In conclusion, the alleviation of UUO-induced RTF in kl/kl mice was due to the TGF-β1 signaling suppression caused by an elevated serum 1, 25(OH)2 vitamin D3.
authors.affiliation: 1] First Department of Pathology, Wakayama Medical University School of Medicine, 811-1 Kimiidera, Wakayama 641-0012, Japan [2] Department of Pathology, School of Medicine, Shandong University, Jinan Wen Hua Xi Road 44, Jinan 250012, PR China.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Pathology, School of Medicine, Shandong University, Jinan Wen Hua Xi Road 44, Jinan 250012, PR China.
authors.forename: Gengyin
authors.initials: G
authors.lastname: Zhou
authors.affiliation: 1] First Department of Pathology, Wakayama Medical University School of Medicine, 811-1 Kimiidera, Wakayama 641-0012, Japan [2].
authors.forename: Ting
authors.initials: T
authors.lastname: Gui
authors.affiliation: First Department of Pathology, Wakayama Medical University School of Medicine, 811-1 Kimiidera, Wakayama 641-0012, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Shimokado
authors.affiliation: First Department of Pathology, Wakayama Medical University School of Medicine, 811-1 Kimiidera, Wakayama 641-0012, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Nakanishi
authors.affiliation: First Department of Pathology, Wakayama Medical University School of Medicine, 811-1 Kimiidera, Wakayama 641-0012, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Oikawa
authors.affiliation: First Department of Pathology, Wakayama Medical University School of Medicine, 811-1 Kimiidera, Wakayama 641-0012, Japan.
authors.forename: Fuyuki
authors.initials: F
authors.lastname: Sato
authors.affiliation: First Department of Pathology, Wakayama Medical University School of Medicine, 811-1 Kimiidera, Wakayama 641-0012, Japan.
authors.forename: Yasuteru
authors.initials: Y
authors.lastname: Muragaki
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000818:Animals; D002117:Calcitriol / Q000097:blood / Q000494:pharmacology*; D002460:Cell Line; D003094:Collagen / Q000096:biosynthesis; D004032:Diet; D004847:Epithelial Cells; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D005966:Glucuronidase / Q000235:genetics; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009395:Nephritis, Interstitial / Q000097:blood / Q000517:prevention & control*; D010710:Phosphates / Q000494:pharmacology; D051436:Renal Insufficiency, Chronic / Q000150:complications; D015398:Signal Transduction / Q000235:genetics; D051900:Smad3 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000473:pathology*
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; C000717428:Fgf23 protein, mouse; D010710:Phosphates; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D003094:Collagen; D005966:Glucuronidase; D000090265:Klotho Proteins; D002117:Calcitriol