Abstract
Angiotensin-converting enzyme 2 (ACE2), its product Angiotensin-(1-7) [Ang-(1-7)], and Ang-(1-7) receptor Mas, have been shown to regulate organogenesis during embryonic development in various species. However, it is not known whether a local ACE2/Ang-(1-7)/Mas axis is present in the fetal pancreas. It is hypothesized that there is a local ACE2/Ang-(1-7)/Mas axis in the embryonic pancreas in mice that is involved in regulating islet cell development. To address this issue, the endogenous expression profile of axis constituents in embryonic mouse pancreata was examined. Involvement of the ACE2 axis in the regulation of pancreatic development was also examined. The present experiments showed in an in vivo animal model that endogenous expression levels of ACE2 and the Mas receptor were upregulated in mouse pancreata in late embryogenesis, peaking on embryonic day E16.5, when it reached 3 folds compared to that seen at E12.5. Consistently, endogenous expression of Ang-(1-7) also peaked at E16.5. Treatment with the ACE2 inhibitor DX600 did not alter islet development. However, prenatal treatment with A779, a Mas receptor antagonist, reduced the β-cell to α-cell ratio in neonatal islets, impaired islet insulin secretory function, and impaired the pups’ glucose tolerance. In ex vivo pancreas explant cultures, A779 again decreased the β-cell to α-cell ratio, apparently through its effects on β-cell proliferation (reduced proliferation shown with Ki67 staining), and also decreased Insulin and Ngn3 mRNA expression. Furthermore, treatment of explant cultures with Ang-(1-7) increased mRNA levels of Insulin and pancreatic progenitor marker Ngn3, as well as Nox4, the ROS generation enzyme; these stimulatory effects were attenuated by co-treatment with A779, suggesting that Ang-(1-7), via Mas receptor signaling, may promote differentiation of pancreatic progenitors into insulin-producing cells via modulation of reactive oxygen species. These data together suggest that a Mas receptor-mediated mechanism may stimulate pancreatic cell development.
Highlights
There is very limited supply of transplantable islet cells and this circumstance impedes the advancement of islet transplantation as a curative treatment for Type 1 diabetes, a chronic disease resulting from the body's failure to produce insulin
Because β-cell replication represents an important mechanism contributing to the expansion of the β-cell population during fetal pancreatic development [19], we investigated whether manipulations of Mas receptor activation affect the proliferation of existing insulin-positive cells and transcription of genes including Insulin and Ngn3
Western blot and real-time PCR studies have shown consistent protein and mRNA expression of both angiotensin-converting enzyme 2 (ACE2) and Mas receptor in embryonic mouse pancreas (Fig 1A–1C), with peak mRNA expression and protein level occurring on E16.5 in both cases
Summary
There is very limited supply of transplantable islet cells and this circumstance impedes the advancement of islet transplantation as a curative treatment for Type 1 diabetes, a chronic disease resulting from the body's failure to produce insulin. The effects of Ang(1–7) are mediated through its G-protein coupled receptor, Mas, which is expressed in several tissues, including the heart, kidney and ovary [6,7]. This newly identified ACE2/Ang-(1–7)/ Mas axis, which is distinct from the classical RAS pathway, is gaining research importance and has been suggested to act as a negative regulator of Ang II signaling, especially in the attenuation of cardiovascular dysfunction and associated metabolic diseases including diabetes [8,9,10,11]
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