High glucose activates the alternative ACE2/Ang-(1-7)/Mas and APN/Ang IV/IRAP RAS axes in pancreatic β-cells

Abstract

The activation of the classical angiotensin (Ang)-converting enzyme (ACE)/Ang II/Ang II type 1 receptor (AT1R) axis of the renin-angiotensin system (RAS) has been associated with islet dysfunction and insulin resistance. Hyperglycaemia, hypertension and obesity, major components of metabolic syndrome, are all associated with increased systemic and tissue levels of Ang II. Whereas it is well established that Ang II, by binding to AT1R, impairs glucose-stimulated insulin secretion and insulin signaling, the contribution of alternative RAS axes to β-cell function remains to be fully elucidated. In this study, using the BRIN-BD11 rat insulinoma cell line, we i) examined the basal expression levels of components of classical and alternative RAS axes and ii) investigated the effects of normal (5.5 mM) and elevated (11, 15, 25 mM) glucose concentrations on their expression and/or enzymatic activity by means of reverse transcription quantitative PCR (RT-qPCR), immunoblot analysis and enzymatic activity assays. The results correlated with the insulin production and release. Essential components of all RAS axes were found to be expressed in the BRIN-BD11 cells. Components of the alternative RAS axes, ACE2, neutral endopeptidase 24.11, Mas receptor (Mas), aminopeptidases A (APA) and N (APN) and insulin-regulated aminopeptidase (IRAP) showed an increased expression/activity in response to high glucose. These alterations were paralleled by the glucose-dependent increase in insulin production and release. By contrast, components of the classical RAS axis, ACE, AT1R and Ang II type 2 receptor (AT2R), remained largely unaffected under these conditions. Glucose induced the activation of the alternative ACE2/Ang-( 1 - 7 )/Mas and APN/Ang IV/IRAP RAS axes simultaneously with the stimulation of insulin production/release. Our data suggest the existence of a functional link between the local RAS axis and pancreatic β-cell function; however, further studies are required to confirm this hypothesis.

Evidence of changes in alpha-1/AT1 receptor function generated by diet-induced obesity

“…3 Then, under diabetic/obesity conditions, endotheliumderived vasodilators may increase their participation as a counter-regulatory mechanism towards homeostasis including an increased participation vasodilator components of RAS as AT2R 4 or angiotensin-converting enzyme 2 (ACE2)-angiotensin 1-7. [5][6][7] Additionally, damage produced by metabolic disturbances can change adrenergic or Ang II receptors functionality, increasing the crosstalk between α 1 and AT1 receptors. [8][9][10][11] Indeed, an increased α 1 /AT1 crosstalk has been proposed as an early damage indicator of metabolic disturbances.…”

ACE2 deficiency reduces β-cell mass and impairs β-cell proliferation in obese C57BL/6 mice

“…Local pancreatic ACE2 may control Ang II levels at islets and serve as an endogenous mechanism to limit RAS activity. Indeed, recent studies suggest that ACE2 is a positive regulator of pancreatic function (13,23), as mice with whole body deficiency of ACE2 became progressively glucose intolerant due to impairments in insulin secretion (35). Moreover, in mice fed a high-fat (HF) diet, whole body ACE2 deficiency deteriorated islet function through a mechanism involving impairment of islet microvasculature (57).…”

Association of Increased Serum ACE Activity with Logical Memory Ability in Type 2 Diabetic Patients with Mild Cognitive Impairment

“…We noticed that our MCI patients had higher levels of HbA1C, which indicated poor glucose control. Hyperglycemia has been shown to increase serum ACE level and activity (Härdtner et al, 2013). In addition, elevated ACE activity could reduce the release of neprilysin (NEP) which acts as an Aβ-degrading enzyme in the brain (Carson and Turner, 2002).…”