The renin-angiotensin system (RAS) 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 hours and by histological examination of the pancreas at 12 hours. In contrast, parenchymal atrophy and fibrosis were more pronounced in AT2-/- mice compared to wt mice at 10 days. Fibrosis was accompanied by activation of pancreatic stellate cells (PSC) evaluated by western blot analysis for -smooth muscle actin (-SMA)and by immunocytochemistry; PSC activation was further increased in AT2-/- mice compared to wt mice. The level of pancreatic transforming growth factor beta1 (TGF-1) 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 anti-fibrogenic 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.