The Angiotensin-(1–7)/Mas Axis Improves Pancreatic β-Cell Function in Vitro and in Vivo

Abstract

The angiotensin-converting enzyme 2/angiotensin (Ang)-(1-7)/Mas axis of the renin-angiotensin system often opposes the detrimental effects of the angiotensin-converting enzyme/Ang II/Ang II type 1 receptor axis and has been associated with beneficial effects on glucose homeostasis, whereas underlying mechanisms are mostly unknown. Here we investigate the effects of Ang-(1-7) and its receptor Mas on β-cell function. Isolated islets from Mas-deficient and wild-type mice were stimulated with Ang-(1-7) or its antagonists and effects on insulin secretion determined. Islets' cytoplasmic calcium and cAMP concentrations, mRNA amounts of Ins1, Ins2, Pdx1, and Mafa and effects of inhibitors of cAMP downstream signaling were determined. Ang-(1-7) was also applied to mice by osmotic pumps for 14 days and effects on glucose tolerance and insulin secretion were assessed. Ang-(1-7) increased insulin secretion from wild-type islets, whereas antagonists and genetic Mas deficiency led to reduced insulin secretion. The Mas-dependent effects of Ang-(1-7) on insulin secretion did not result from changes in insulin gene expression or changes in the excitation-secretion coupling but from increased intracellular cAMP involving exchange protein activated directly by cAMP. Administration of Ang-(1-7) in vivo had only marginal effects on glucose tolerance in wild-type mice but still resulted in improved insulin secretion from islets isolated of these mice. Interestingly, although less pronounced than in wild types, Ang-(1-7) still affected insulin secretion in Mas-deficient islets. The data indicate a significant function of Ang-(1-7) in the regulation of insulin secretion from mouse islets in vitro and in vivo, mainly, but not exclusively, by Mas-dependent signaling, modulating the accessory pathway of insulin secretion via increase in cAMP.

Neprilysin Is Required for Angiotensin-(1–7)’s Ability to Enhance Insulin Secretion via Its Proteolytic Activity to Generate Angiotensin-(1–2)

“…In fact, neprilysin hydrolyzes angiotensin I to angiotensin-(1–7) with greater efficiency than ACE2 (1). In comparing the expression pattern of neprilysin to ACE2 in islets, we (12) and others (21) have demonstrated that neprilysin is more widespread, because it is in both β-cells and non–β-cells. We show that ACE2 is limited to α, δ, and PP cells, which is in keeping with a recent report (22).…”

“…Other histological reports do not clearly define the islet cell types expressing ACE2 (11,23–25). One study (26) showed that ACE2 colocalized with both insulin and somatostatin, but rarely with glucagon and PP, whereas another study (21) showed ACE2 colocalized primarily with insulin. Inconsistency in descriptions of islet ACE2 localization could be due to species-specific differences in ACE2 expression.…”

“…However, when continuously infused in mice for 10 days, angiotensin-(1–7) failed to enhance the insulin response to oral glucose. Interestingly, when studied ex vivo, islets from these mice demonstrated increased GSIS even without further angiotensin-(1–7) exposure in culture (21). These findings were attributed to both MasR-dependent and MasR-independent mechanisms modulating insulin secretion via increased cAMP.…”

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

“…"Clearly, the development of the first antagonists with (subtype) selectivity for EPAC represents another research milestone to ascribe biologic responses to EPAC" (915). Indeed, these selective EPAC2 inhibitors are becoming effective tools in probing isoform-specific EPAC functions (18,47,130,175,226,250,302,411,463,565,682,743,841,896,961,1114).…”

Significance of angiotensin 1–7 coupling with MAS1 receptor and other GPCRs to the renin‐angiotensin system: IUPHAR Review 22

“…Ang(1–7) reverses hyperglycaemia and its consequences in an animal model of type 2 diabetes (Santos et al, ). Ang(1–7) regulates insulin secretion through a MAS‐dependent cAMP signalling pathway (Sahr et al, ).…”