title: Natriuretic peptide/natriuretic peptide receptor-A (NPR-A) system has inhibitory effects in renal fibrosis in mice.
abstract: OBJECTIVE
  This study was designed to examine whether natriuretic peptide/natriuretic peptide receptor-A (NPR-A) system attenuates renal fibrosis in a unilateral ureteral obstruction (UUO) model and also examined the mechanism involved.
  
  
  METHODS
  Three groups were studied: untreated UUO in wild-type mice; untreated UUO in NPR-A KO mice; and ANP treated (0.05 microg/kg/min) UUO in wild-type mice. We measured histological and immunohistochemical findings (alpha-SMA and F4/80), tissue cGMP levels, various mRNA expression levels by real-time PCR analysis, and transcription factor levels (AP-1 and NF-kappaB) in renal tissue.
  
  
  RESULTS
  Compared with wild-type UUO mice, NPRA-KO UUO mice had abnormal morphological findings (fibrous area: +26%, alpha-SMA expression: +30%) with lower tissue cGMP levels and increases in the mRNA expression levels of TGF-beta, collagen I, collagen III, PAI-1, renin and angiotensinogen, whereas there were no differences in F4/80 positive cells or the mRNA expression levels of ICAM-1, osteopontin, or MCP-1 between the two groups. In contrast, ANP pre-treatment significantly improved morphological changes with increase of tissue cGMP levels and reduction in the mRNA expression level of TGF-beta, collagen I, collagen III, PAI-1, ICAM-1, osteopontin, MCP-1, renin, and angiotensinogen. NPRA-KO UUO mice had higher AP-1 levels than wild-type UUO mice and ANP pre-treatment reduced AP-1 and NF-kappaB activity.
  
  
  CONCLUSIONS
  The endogenous natriuretic peptide/NPR-A system may inhibit renal fibrosis partly via inhibition of the angiotensin/AP-1/TGF-beta/collagen pathway and exogenous ANP pre-treatment may inhibit it partly via both the angiotensin/AP-1/TGF-beta/collagen and NF-kappaB/inflammatory pathways.
authors.affiliation: Department of Hypertension and Cardiorenal Medicine, Dokkyo Medical University, Mibu, Tochigi 321-0293, Japan. nishikim@dokkyomed.ac.jp
authors.forename: Toshio
authors.initials: T
authors.lastname: Nishikimi
authors.forename: Chikako
authors.initials: C
authors.lastname: Inaba-Iemura
authors.forename: Kimihiko
authors.initials: K
authors.lastname: Ishimura
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Tadokoro
authors.forename: Shogo
authors.initials: S
authors.lastname: Koshikawa
authors.forename: Keiko
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Kazumi
authors.initials: K
authors.lastname: Akimoto
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Hattori
authors.forename: Kikuo
authors.initials: K
authors.lastname: Kasai
authors.forename: Naoto
authors.initials: N
authors.lastname: Minamino
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Maeda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsuoka
mesh_terms: D000818:Animals; D003433:Crosses, Genetic; D006152:Cyclic GMP / Q000032:analysis; D005355:Fibrosis / Q000473:pathology; D005456:Fluorescent Dyes / Q000378:metabolism; D007150:Immunohistochemistry; D007211:Indoles / Q000378:metabolism; D007674:Kidney Diseases / Q000209:etiology* / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D045265:Natriuretic Peptides / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System; D014517:Ureteral Obstruction / Q000150:complications*
chemical_list: D005456:Fluorescent Dyes; D007211:Indoles; D045265:Natriuretic Peptides; D012333:RNA, Messenger; C007293:DAPI; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D006152:Cyclic GMP