title: 22-Oxacalcitriol prevents progression of peritoneal fibrosis in a mouse model.
abstract: OBJECTIVE
  Vitamin D plays an important role in calcium homeostasis and is used to treat secondary hyperparathyroidism among dialysis patients. The biologic activity of vitamin D and its analogs is mediated by vitamin D receptor (VDR), which is distributed widely throughout the body. Recent papers have revealed that low vitamin D levels are correlated with severe fibrosis in chronic diseases, including cystic fibrosis and hepatitis. The aim of the present study was to evaluate the protective effects of vitamin D against the progression of peritoneal fibrosis.
  
  
  METHODS
  Peritoneal fibrosis was induced by injection of chlorhexidine gluconate (CG) into the peritoneal cavity of mice every other day for 3 weeks. An analog of vitamin D, 22-oxacalcitriol (OCT), was administered subcutaneously daily from initiation of the CG injections. The peritoneal tissue was excised at 3 weeks. Changes in morphology were assessed by hematoxylin and eosin staining. Expression of VDR, alpha smooth muscle actin (as a marker of myofibroblasts), type III collagen, transforming growth factor β(TGF-β), phosphorylated Smad2/3, F4/80 (as a marker of macrophages), and monocyte chemoattractant protein-1 (MCP-1) was examined by immunohistochemistry. Southwestern histochemistry was used to detect activated nuclear factor κB (NF-κB).
  
  
  RESULTS
  In the CG-injected mice, immunohistochemical analysis revealed expression of VDR in mesothelial cells, myofibroblasts, and macrophages in the thickened submesothelial zone. Treatment with OCT significantly prevented peritoneal fibrosis and reduced the accumulation of type III collagen in CG-treated mice. Among the markers of fibrosis, the numbers of myofibroblasts, cells positive for TGF-β, and cells positive for phosphorylated Smad2/3 were significantly decreased in the OCT-treated group compared with the vehicle-treated group. Furthermore, OCT suppressed inflammatory mediators of fibrosis, as shown by the reduced numbers of activated NF-κB cells, macrophages, and MCP-1-expressing cells.
  
  
  CONCLUSIONS
  Our results indicate that OCT attenuates peritoneal fibrosis, an effect accompanied by reduced numbers of myofibroblasts, infiltrating macrophages, and TGF-β-positive cells, suggesting that vitamin D has potential as a novel therapeutic agent for preventing peritoneal sclerosis.
authors.affiliation: Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Misaki
authors.initials: M
authors.lastname: Hirose
authors.forename: Tomoya
authors.initials: T
authors.lastname: Nishino
authors.forename: Yoko
authors.initials: Y
authors.lastname: Obata
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nakazawa
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nakazawa
authors.forename: Akira
authors.initials: A
authors.lastname: Furusu
authors.forename: Katsushige
authors.initials: K
authors.lastname: Abe
authors.forename: Masanobu
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Takehiko
authors.initials: T
authors.lastname: Koji
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kohno
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018932:Chemokine CCL2 / Q000378:metabolism; D002710:Chlorhexidine / Q000031:analogs & derivatives; D024061:Collagen Type III / Q000378:metabolism; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D010530:Peritoneal Dialysis / Q000009:adverse effects; D056627:Peritoneal Fibrosis / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control*; D018167:Receptors, Calcitriol / Q000378:metabolism; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014815:Vitamins / Q000627:therapeutic use*
chemical_list: D000199:Actins; D018932:Chemokine CCL2; D024061:Collagen Type III; D018167:Receptors, Calcitriol; D051896:Smad Proteins, Receptor-Regulated; D016212:Transforming Growth Factor beta; D014815:Vitamins; D002117:Calcitriol; C010882:chlorhexidine gluconate; C051883:maxacalcitol; D002710:Chlorhexidine