title: Deficiency of endothelial nitric oxide signaling pathway exacerbates peritoneal fibrosis in mice.
abstract: BACKGROUND
  Long-term peritoneal dialysis (PD) causes peritoneal dysfunction and structural alterations, eventually leading to peritoneal fibrosis. The endothelial nitric oxide synthase (eNOS)-NO signaling pathway contributes to the progression of organ fibrosis. However, it remains unknown whether NO signaling is involved in the process of peritoneal fibrosis. We evaluated the role of the eNOS-NO signaling pathway in the development of peritoneal fibrosis and whether stimulation of soluble guanylate cyclase (sGC), a downstream effector of NO, could attenuate peritoneal fibrosis.
  
  
  METHODS
  We used wild-type (WT) and eNOS-deficient mice (eNOSKO). The mice underwent mechanical peritoneal stripping-induced peritoneal fibrosis at day 0. At 3, 7, 14, and 28 days after peritoneal stripping, the mice were killed. In some eNOSKO mice, the sGC stimulator Bay 41-2272 was administered by intraperitoneal injection.
  
  
  RESULTS
  In WT mice, granulomatous tissue formation was observed in the submesothelial area at days 3 and 7. After day 7, the peritoneal membrane thickness gradually decreased and peritoneal tissue was repaired with leaving only slight fibrosis at day 28. However, eNOSKO mice demonstrated more progression of peritoneal fibrosis than WT mice at 28 days after peritoneal stripping. Expression of vimentin in the thickened peritoneum was prolonged after day 7 in eNOSKO mice. Treatment with Bay 41-2272 significantly attenuated peritoneal vimentin expression and fibrosis in the eNOSKO mice.
  
  
  CONCLUSIONS
  Disruption of the eNOS-NO signaling pathway exacerbates peritoneal fibrosis by delaying wound healing. sGC stimulation may be a useful therapy for prevention of peritoneal fibrosis.
authors.affiliation: Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, 701-0192, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kadoya
authors.forename: Minoru
authors.initials: M
authors.lastname: Satoh
authors.forename: Hajime
authors.initials: H
authors.lastname: Nagasu
authors.forename: Tamaki
authors.initials: T
authors.lastname: Sasaki
authors.forename: Naoki
authors.initials: N
authors.lastname: Kashihara
mesh_terms: D000818:Animals; D005355:Fibrosis; D006162:Guanylate Cyclase / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D007633:Keratins / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010530:Peritoneal Dialysis / Q000009:adverse effects; D056627:Peritoneal Fibrosis / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control; D010537:Peritoneum / Q000201:enzymology / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase; D014746:Vimentin / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D018160:Receptors, Cytoplasmic and Nuclear; D014746:Vimentin; D009569:Nitric Oxide; D007633:Keratins; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase