Angiotensin II Type 2 Receptor Regulates the Development of Pancreatic Endocrine Cells in Mouse Embryos

Background: We previously identified a local renin-angiotensin system (RAS) regulating the differentiation of an isolated population of human pancreatic progenitor cells. Major RAS components that regulate organogenesis have been also described in embryos; however, it is not known whether a local RAS is present in the fetal pancreas. We now hypothesize that angiotensin II type 1 (AT(1)) and type 2 (AT(2)) receptors are expressed in mouse embryonic pancreas and involved in regulating endocrine cell development.Results: Differential expression of AT(1) and AT(2) receptors was observed in the mouse pancreata in late embryogenesis. Systemic AT(2), but not AT(1), receptor blockade during the second transition in pancreatic development (from embryonic day 12.0 onward) reduced the -cell to -cell ratio of the neonate islets, impaired their insulin secretory function and the glucose tolerance of the pups. Studies with pancreas explants ex vivo revealed regulation by AT(2) receptors of the differentiation of pancreatic progenitors into insulin-producing cells and of the proliferation of the differentiated cell, actions that did not result from reduced angiogenesis as a secondary effect of AT(2) receptor antagonism.Conclusions: These data revealed an AT(2) receptor-mediated mechanism regulating pancreatic endocrine cell development in vivo. Developmental Dynamics 243:415-427, 2014. (c) 2013 Wiley Periodicals, Inc.