Upregulation of ACE2-ANG-(1–7)-Mas axis in jejunal enterocytes of type 1 diabetic rats: implications for glucose transport

Abstract

The inhibitory effects of the angiotensin-converting enzyme (ACE)-ANG II-angiotensin type 1 (AT₁) receptor axis on jejunal glucose uptake and the reduced expression of this system in type 1 diabetes mellitus (T1DM) have been documented previously. The ACE2-ANG-(1-7)-Mas receptor axis is thought to oppose the actions of the ACE-ANG II-AT₁ receptor axis in heart, liver, and kidney. However, the possible involvement of the ACE2-ANG-(1-7)-Mas receptor system on enhanced jejunal glucose transport in T1DM has yet to be determined. Rat everted jejunum and Caco-2 cells were used to determine the effects of ANG-(1-7) on glucose uptake and to study the ACE2-ANG-(1-7)-Mas receptor signaling pathway. Expression of target gene and protein in jejunal enterocytes and human Caco-2 cells were quantified using real-time PCR and Western blotting. T1DM increased jejunal protein and mRNA expression of ACE2 (by 59 and 173%, respectively) and Mas receptor (by 55 and 100%, respectively) in jejunum. One millimolar ANG-(1-7) reduced glucose uptake in jejunum and Caco-2 cells by 30.6 and 30.3%, respectively, effects that were abolished following addition of 1 μM A-779 (a Mas receptor blocker) or 1 μM GF-109203X (protein kinase C inhibitor) to incubation buffer for jejunum or Caco-2 cells, respectively. Finally, intravenous treatment of animals with ANG-(1-7) significantly improved oral glucose tolerance in T1DM but not control animals. In conclusion, enhanced activity of the ACE2-ANG-(1-7)-Mas receptor axis in jejunal enterocytes is likely to moderate the T1DM-induced increase in jejunal glucose uptake resulting from downregulation of the ACE-ANG II-AT₁ receptor axis. Therefore, altered activity of both ACE and ACE2 systems during diabetes will determine the overall rate of glucose transport across the jejunal epithelium.

Local expression of AP/AngIV/IRAP and effect of AngIV on glucose-induced epithelial transport in human jejunal mucosa

“…13,40 It can be suspected that mucosal expression and the function of RAS during pathophysiological conditions, for example, in diabetes or inflammatory bowel disease, differ considerably from the healthy (physiological) individuals studied in the present study. Thus, in order to extend the influence of the classic and alternative RAS pathways under certain pathological mucosal conditions, or diabetes, in humans further investigation is warranted.…”

“…12 In this situation the expression of the ACE2/Ang(1-7)/MasR axis was up-regulated resulting in reduced epithelial glucose uptake. 13 The authors interpreted the up-regulation of ACE2/Ang(1-7)/ MasR axis as a compensatory response to the lowered classic RAS-/AT1R-mediated inhibition of mucosal glucose absorption. 13 Apparently, the RAS system provides at least two pathways for the local control of enterocyte glucose transport, and in the present paper we propose the existence of a third one: the AngIV/IRAP axis.…”

“…15 However, in addition to the classic angiotensin-converting enzyme (ACE)-AngII axis acting on AT1R and AT2R, there are evidently a number of other angiotensins with biological actions, for example, the ACE2-Ang(1-7) axis acting primarily via the Mas receptor. 13 Another RAS pathway starts with formation of Angiotensin III (AngIII) from degradation of AngII by glutamyl aminopeptidase (AP-A; EC 3.4.11.7), cleaving the Asp1-Arg2 bond. 16,17 Angiotensin IV (AngIV) is then generated by the enzyme arginine aminopeptidase (AP-B; EC 3.4.11.6) or alanyl aminopeptidase (AP-M; also termed aminopeptidase-N; EC 3.4.11.2), eliminating arginine from the N-terminus of AngIII.…”

Multifaceted interplay among mediators and regulators of intestinal glucose absorption: potential impacts on diabetes research and treatment

“…Ang-(1-7) is generated, primarily, from the processing of AngI or AngII by prolyl-endopeptidase or from the processing of AngII by carboxypeptidase (58,103,105,154). In the context of intestinal glucose uptake, recent experiments in our laboratory showed that enterocyte levels of Ang-(1-7), ACE, and the Mas receptor are elevated in T1DM patients, with Ang-(1-7) inhibiting Mas receptor-mediated jejunal glucose uptake in a dose-dependent manner (170). Given that AngII has been reported to inhibit ACE2 formation (46,47), these recent findings complement our previous results in T1DM model rats showing that diminished ACE and AT1R expression in T1DM reduced enterocyte production of AngII (169), which in turn increased expression of ACE2 and Ang-(1-7), resulting in an upregulated ACE2-Ang-(1-7)-Mas axis in jejunal enterocytes.…”

“…We conducted follow-up experiments examining the cellular signaling mechanism underlying Ang-(1-7)'s inhibition of enterocyte glucose uptake and found that the effect is dependent on Ang-(1-7) binding of the Mas receptor (i.e., blocked by Mas receptor antagonist A-779) and downstream activation of PKC (i.e., blocked by PKC inhibitor GF-109203X hydrochloride) (170). The underlying mechanistic relationship between Mas receptor activation, PKC activation, and a blunted SGLT-mediated glucose transport in the jejunum has yet to be delineated.…”