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. 2017 Dec 29;15(1):97.
doi: 10.1186/s12958-017-0316-8.

The role of ACE2, angiotensin-(1-7) and Mas1 receptor axis in glucocorticoid-induced intrauterine growth restriction

Elham Ghadhanfar  1 , Aseel Alsalem  2 , Shaimaa Al-Kandari  2 , Jumana Naser  2 , Fawzi Babiker  1 , Maie Al-Bader  3
Affiliations

The role of ACE2, angiotensin-(1-7) and Mas1 receptor axis in glucocorticoid-induced intrauterine growth restriction

Elham Ghadhanfar et al. Reprod Biol Endocrinol. .

Expression of concern in

Abstract

Background: Plasma and urine levels of the potent vasodilator Ang-(1-7) are elevated in mid and late pregnancy and are correlated with elevated placental angiogenesis, fetal blood flow, and rapid fetal growth. We hypothesized that Ang-(1-7), its receptor (Mas1) and the enzymes involved in Ang-(1-7) production (ACE2 and Membrane metallo-endopeptidase; MME) are down regulated in response to glucocorticoid administration contributing to IUGR.

Methods: Pregnant female Sprague-Dawley rats were injected with dexamethasone (DEX; 0.4 mg/kg/day) starting from 14 day gestation (dg) till sacrifice at 19 or 21 dg while control groups were injected with saline (n = 6/group). The gene and protein expression of ACE2, MME, Ang-(1-7) and Mas1 receptor in the placental labyrinth (LZ) and basal zones (BZ) were studied.

Results: DEX administration caused a reduction in LZ weight at 19 and 21 dg (p < 0.001). IUGR, as shown by decreased fetal weights, was evident in DEX treated rats at 21 dg (p < 0.01). ACE2 gene expression was elevated in the LZ of control placentas at 21 dg (p < 0.01) compared to 19 dg and DEX prevented this rise at both gene (p < 0.01) and protein levels (p < 0.05). In addition, Ang-(1-7) protein expression in LZ was significantly reduced in DEX treated rats at 21 dg (p < 0.05). On the other hand, Mas1 and MME were upregulated in LZ at 21 dg in both groups (p < 0.05 and p < 0.001, respectively).

Conclusion: The results of this study indicate that a reduced expression of ACE2 and Ang-(1-7) in the placenta by DEX treatment may be responsible for IUGR and consequent disease programming later in life.

Keywords: ACE2; Ang-(1–7); Dexamethasone; IUGR; MME; Mas1 receptor.

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Conflict of interest statement

Authors’ information

Department of Physiology, Faculty of Medicine, Kuwait University.

Ethics approval and consent to participate

All procedures used in this study were approved by the Animal Welfare Committee at Kuwait University Health Sciences Center.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1
Fig. 1
Components of the renin-angiotensin system (RAS); Ang II and Ang-(1–7), their receptors and the enzymes involved in the production pathways. Bold arrow shows the major pathway. ACE, Angiotensin 1-converting enzyme; ACE2, Angiotensin 1-converting enzyme2; MME, Membrane metallo-endopeptidase; AT1, Angiotensin II type 1 receptor; AT2, Angiotensin II type 2 receptor. Modified from [41]
Fig. 2
Fig. 2
Gross data analysis of controls (open bars) and DEX-treated (solid bars) rats at 19 dg and 21 dg. Data analyzed were Litter number (a), average fetal body weight (b), placental weight (c), labyrinth (d) and basal (e) zones weights and placental efficiency (f). Error bars represent the mean ± SEM (n = 6 per group). ***p < 0.001 compared with 19 dg of same group. ##p < 0.01 compared with untreated rats at same gestational day
Fig. 3
Fig. 3
Quantitative real-time PCR analysis (2-∆∆Ct values) of ACE2, Mas1 and MME gene expression in basal (a-c) and labyrinth (d-f) zones. Open bars denote controls while solid bars are DEX-treated rats. Error bars represent the mean ± SEM (n = 6 per group). *p < 0.05, **p < 0.01, ***p < 0.001 compared with 19 dg of same group. ##p < 0.01, ###p < 0.001 compared with untreated rats at the same gestational day
Fig. 4
Fig. 4
Western blot analysis of Mas1 receptor (a) and MME (b) in basal zone of the placenta. (c-f) represent the western blot analysis of ACE2, Ang-(1–7), Mas1 and MME in the placental labyrinth zone. Open bars denote controls while solid bars are DEX-treated rats. Error bars represent the mean ± SEM (n = 6 per group). *p < 0.05, **p < 0.01 compared with 19 dg of same group. #p < 0.05, ##p < 0.01, ###p < 0.001 compared with untreated rats at the same gestational day
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