title: Angiotensin II type 1 receptor interaction is an important regulator for the development of pancreatic fibrosis in mice.
abstract: The renin-angiotensin system (RAS) plays important roles in various pathophysiological processes. However, the role of the RAS in pancreatic fibrosis has not been established. We investigated the role of angiotensin II (ANG II)-ANG II type 1 (AT(1)) receptor pathway in the development of pancreatic fibrosis with AT(1a) receptor-deficient [AT(1a)(-/-)] mice. To induce pancreatic fibrosis, AT(1a)(-/-) and wild-type (WT) mice were submitted to three episodes of acute pancreatitis induced by six intraperitoneal injections of 50 microg/kg body wt cerulein at hourly intervals, per week, for four consecutive weeks. Pancreatic fibrosis was assessed by histology and hydroxyproline content. Pancreatic stellate cell (PSC) activation and the localization of AT(1) receptors were assessed by Western blot analysis for alpha-smooth muscle actin and immunostaining. Transforming growth factor-beta(1) (TGF-beta(1)) mRNA expression in the pancreas was assessed by RT-PCR. Six intraperitoneal injections of cerulein induced acute pancreatitis in both AT(1a)(-/-) and WT mice. There were no significant differences between two groups with regard to serum amylase and histological changes. Pancreatic fibrosis induced by repeated episodes of acute pancreatitis was significantly attenuated in AT(1a)(-/-) mice compared with that in WT mice. This finding was accompanied by a reduction of activated PSCs. Dual-immunofluorescence staining in WT mice revealed that activated PSCs express AT(1) receptors. The level of TGF-beta(1) mRNA was lower in AT(1a)(-/-) mice than in WT mice. Our results demonstrate that the ANG II-AT(1) receptor pathway is not essential for the local pancreatic injury in acute pancreatitis but plays an important role in the development of pancreatic fibrosis through PSC activation and proliferation.
authors.affiliation: Third Dept. of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan.
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Nagashio
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asaumi
authors.forename: Shiro
authors.initials: S
authors.lastname: Watanabe
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nomiyama
authors.forename: Masashi
authors.initials: M
authors.lastname: Taguchi
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Tashiro
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sugaya
authors.forename: Makoto
authors.initials: M
authors.lastname: Otsuki
mesh_terms: D000818:Animals; D002108:Ceruletide; D005355:Fibrosis; D006909:Hydroxyproline / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010182:Pancreatic Diseases / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D012008:Recurrence; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D002108:Ceruletide; D006909:Hydroxyproline