The angiotensin-converting enzyme 2/angiotensin (1–7)/Mas axis protects the function of pancreatic β cells by improving the function of islet microvascular endothelial cells

Abstract

In the diabetic state, the local rennin-angiotensin system (RAS) is activated in the pancreas, and is strongly associated with islet dysfunction. The angiotensin-converting enzyme 2 (ACE2)/angiotensin (1-7) [Ang(1-7)]/Mas axis is a protective, negative regulator of the classical renin-angiotensin system. In this study, we assessed the role of the ACE2/Ang(1‑7)/Mas axis in pancreatic β cell survival and function. ACE2 knockout and wild-type mice were fed a high-fat diet for 16 weeks. We then performed terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assays, and determined the expression levels of interleukin-1β (IL-1β) and inducible nitric oxide synthase (iNOS) in the pancreatic islets. The effects of Ang(1-7) or Mas receptor silencing on endothelial function were assessed in MS-1 cells. MIN6 cells were then co-cultured with the MS-1 cells to evaluate the effects of ACE2 on insulin secretion. The ACE2 knockout mice were more susceptible than the wild-type mice to high-fat diet-induced β cell dysfunction. The TUNEL-positive area of the pancreatic islets and the expression levels of IL-1β and iNOS were markedly increased in the ACE2 knockout mice compared with their wild-type littermates. The Mas-silenced MS-1 cells were more sensitive to palmitate-induced dysfunction and apoptosis in vitro. Ang(1-7) increased the activity of the Akt/endothelial NOS/nitric oxide (NO) pathway in the MS-1 cells, protected MIN6 cells against palmitate-induced apoptosis, and improved MIN6 insulin secretory function in the co-culture system. In conclusion, this study demonstrates that the ACE2/Ang(1-7)/Mas axis is a potential target for protecting the funcion of β cells by improving the function of islet microvascular endothelial cells.

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

“…These findings were attributed to both MasR-dependent and MasR-independent mechanisms modulating insulin secretion via increased cAMP. In other studies using β-cells cocultured with islet endothelial cells (17) or diabetic rats (18), angiotensin-(1–7)–mediated improvements in GSIS were associated with enhanced islet endothelial cell function and pancreatic microcirculation. Given that our in vitro study design involved islet culture with peptides for up to 48 h and that the majority of endothelial cells are typically lost during this period in culture (27), it is unlikely that the islet microvasculature played a significant role in the increased insulin secretion we observed with angiotensin peptides.…”

Regulation of insulin sensitivity, insulin production, and pancreatic β cell survival by angiotensin-(1-7) in a rat model of streptozotocin-induced diabetes mellitus

“…Ang-(1-7) has been found to attenuate STZ-induced diabetic renal injury through the Mas receptor [35]. A recent study has revealed that the Ang-(1-7)/Mas axis protects pancreatic ␤ cells from high-fat diet-induced dysfunction through improving the function of islet microvascular endothelial cells [11]. In agreement with this study, we found that Ang-(1-7) administration improved the survival of pancreatic ␤ cells in STZ-induced diabetic rats.…”

Hypertension, Thrombosis, Kidney Failure, and Diabetes: Is COVID-19 an Endothelial Disease? A Comprehensive Evaluation of Clinical and Basic Evidence

“…This aspect is really limiting, because diabetes and altered glucose homeostasis during a condition of severe pneumonia with SARS are reported as main factors of worse prognosis and death [152]. COVID-19 could also induce new onset diabetes, by augmenting insulin resistance and/or by a direct action [155] on the islets of Langerhans; supporting this view, previous studies have shown that ACE2 can be a therapeutic target to ameliorate microcirculation in the islets [156], and ACE2 is known to be expressed by pancreatic beta cells [157][158][159][160][161][162].…”