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This Article Full Text Full Text (PDF) All Versions of this Article: 296/2/G284    most recent 90409.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ulmasov, B. Articles by Neuschwander-Tetri, B. A. Search for Related Content PubMed PubMed Citation Articles by Ulmasov, B. Articles by Neuschwander-Tetri, B. A.

LIVER AND BILIARY TRACT

Protective role of angiotensin II type 2 receptor signaling in a mouse model of pancreatic fibrosis

¹Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, Missouri; ²Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; ³Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee

Submitted 1 July 2008 ; accepted in final form 20 November 2008

The renin-angiotensin system contributes to pathological processes in a variety of organs. In the pancreas, blocking the angiotensin II (AII) type 1 receptor (AT1) attenuates pancreatic fibrogenesis in animal models of pancreatitis. Because the role of the AII type 2 receptor (AT2) in modulating pancreatic injury is unknown we investigated the role of AT2 in pancreatic injury and fibrosis. Pancreatic fibrosis was induced by repetitive cerulein administration in C57BL/6 wild-type (WT) or AT2-deficient (AT2–/–) mice and assessed by morphology and gene expression at 10 days. There was no difference between WT and AT2–/– mice in the degree of acute pancreatic injury as assessed by amylase release at 9 and 12 h and by histological examination of the pancreas at 12 h. In contrast, parenchymal atrophy and fibrosis were more pronounced in AT2–/– mice compared with WT mice at 10 days. Fibrosis was accompanied by activation of pancreatic stellate cells (PSC) evaluated by Western blot analysis for -smooth muscle actin and by immunocytochemistry; PSC activation was further increased in AT2–/– mice compared with WT mice. The level of pancreatic transforming growth factor-β1 mRNA and protein after repetitive cerulein treatment was higher in AT2–/– mice than in WT mice. Our results demonstrate that, in contrast to AT1 receptor signaling, AT2 receptor signaling modulates protective antifibrogenic effects in a mouse model of cerulein-induced pancreatic fibrogenesis. We propose that the effects of AII on injury-induced pancreatic fibrosis may be determined by the balance between AT1 and AT2 receptor signaling.

renin-angiotensin system; transforming growth factor-β1; pancreatitis