title: 22-Oxacalcitriol prevents progression of endothelial dysfunction through antioxidative effects in rats with type 2 diabetes and early-stage nephropathy.
abstract: BACKGROUND
  Vitamin D deficiency is associated with endothelial dysfunction in type 2 diabetes patients, but the effectiveness of vitamin D supplementation remains controversial. We assessed whether 22-oxacalcitriol (OCT) could prevent endothelial dysfunction in type 2 diabetes mellitus (DM) rats.
  
  
  METHODS
  DM rats with early-stage nephropathy were treated for 10 weeks with OCT (0.2 μg/kg) three times per week or by an implanted insulin pellet. Endothelial dysfunction was assessed by femoral flow-mediated dilation (FMD).
  
  
  RESULTS
  Insulin significantly improved FMD as blood glucose levels normalized. OCT also improved FMD without hypercalcemia or hyperphosphatemia and without affecting blood glucose or blood pressure. In femoral arteries, OCT significantly suppressed the elevated expression of p22(phox), a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit, and improved the endothelial nitric oxide synthase (eNOS) dimer-to-monomer ratio. In cultured endothelial cells, OCT significantly inhibited high-glucose (HG)-induced reactive oxygen species (ROS) production. Simultaneously, OCT significantly suppressed HG-induced p22(phox) expression and improved eNOS uncoupling as was observed in the in vivo study.
  
  
  CONCLUSIONS
  In DM rats, OCT improved endothelial dysfunction, at least in part, by suppressing ROS generation through p22(phox) expression, which might contribute to improving eNOS uncoupling.
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka, Japan.
authors.forename: Michinori
authors.initials: M
authors.lastname: Hirata
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Serizawa
authors.forename: Ken
authors.initials: K
authors.lastname: Aizawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Yogo
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Tashiro
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takeda
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Moriguchi
authors.forename: Koichi
authors.initials: K
authors.lastname: Endo
authors.forename: Masafumi
authors.initials: M
authors.lastname: Fukagawa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007674:Kidney Diseases / Q000503:physiopathology*; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; D002117:Calcitriol; C051883:maxacalcitol