title: Excess 25-hydroxyvitamin D3 exacerbates tubulointerstitial injury in mice by modulating macrophage phenotype.
abstract: Vitamin D hydroxylated at carbon 25 (25(OH)D) is generally recognized as a precursor of active vitamin D. Despite its low affinity for the vitamin D receptor (VDR), both deficient and excessive 25(OH)D levels are associated with poor clinical outcomes. Here we studied direct effects of 25(OH)D3 on the kidney using 25(OH)D-1α-hydroxylase (CYP27B1) knockout mice. The effects of 25(OH)D3 on unilateral ureteral obstruction were analyzed as proximal tubular cells and macrophages are two major cell types that take up 25(OH)D and contribute to the pathogenesis of kidney injury. Excess 25(OH)D3 in obstructed mice worsened oxidative stress and tubulointerstitial fibrosis, whereas moderate levels of 25(OH)D3 had no effects. The exacerbating effects of excess 25(OH)D3 were abolished in CYP27B1/VDR double-knockout mice and in macrophage-depleted CYP27B1 knockout mice. Excess 25(OH)D3 upregulated both M1 marker (TNF-α) and M2 marker (TGF-β1) levels of kidney-infiltrating macrophages. In vitro analyses verified that excess 25(OH)D3 directly upregulated TNF-α and TGF-β1 in cultured macrophages but not in tubular cells. TNF-α and 25(OH)D3 cooperatively induced oxidative stress by upregulating iNOS in tubular cells. Aggravated tubulointerstitial fibrosis in mice with excess 25(OH)D3 indicated that macrophage-derived TGF-β1 also had a key role in the pathogenesis of surplus 25(OH)D3. Thus, excess 25(OH)D3 worsens tubulointerstitial injury by modulating macrophage phenotype.
authors.affiliation: Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Kusunoki
authors.affiliation: Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Matsui
authors.affiliation: Department of Comprehensive Kidney Disease Research, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hamano
authors.affiliation: Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Shimomura
authors.affiliation: Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Mori
authors.affiliation: Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Sayoko
authors.initials: S
authors.lastname: Yonemoto
authors.affiliation: Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Takabatake
authors.affiliation: Department of Comprehensive Kidney Disease Research, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Tsubakihara
authors.affiliation: Research Unit, Shriners Hospital for Children, Montreal, Quebec, Canada.|Departments of Human Genetics, Surgery, and Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: René
authors.initials: R
authors.lastname: St-Arnaud
authors.affiliation: Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Isaka
authors.affiliation: Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics; D000818:Animals; D002112:Calcifediol / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D005260:Female; D005355:Fibrosis; D007684:Kidney Tubules / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010641:Phenotype; D018167:Receptors, Calcitriol / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014517:Ureteral Obstruction / Q000150:complications
chemical_list: D018167:Receptors, Calcitriol; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002112:Calcifediol