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HORMONES AND SIGNALING

Angiotensin II type 1 receptor interaction is an important regulator for the development of pancreatic fibrosis in mice

¹Third Department of Internal Medicine, University of Occupational and Environmental Health, Japan, School of Medicine, Kitakyushu 807-8555; and ²Discovery and Pharmacology Research Laboratories, Tanabe Seiyaku, Kashima, Osaka 532-8505, Japan

Submitted 7 January 2004 ; accepted in final form 10 March 2004

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 (AT₁) 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 µg/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 AT₁ receptors were assessed by Western blot analysis for -smooth muscle actin and immunostaining. Transforming growth factor-₁ (TGF-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 AT₁ receptors. The level of TGF-₁ mRNA was lower in AT_1a(–/–) mice than in WT mice. Our results demonstrate that the ANG II-AT₁ 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.

pancreatic stellate cells; renin-angiotensin system; transforming growth factor-₁

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