The role of ACE2, angiotensin-(1–7) and Mas1 receptor axis in glucocorticoid-induced intrauterine growth restriction
Authors: Maie Al-Bader
Aseel Alsalem
Elham Ghadhanfar
Shaimaa Al-Kandari
Jumana Naser
Fawzi Babiker
Journal: Reproductive Biology and Endocrinology (2017)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: ACE2; Ang-(1–7); Dexamethasone; IUGR; MME
Affiliations: Department of Physiology, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait., Faculty of Medicine, Kuwait University, Kuwait City, Kuwait., Department of Physiology, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait. .

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

Retracted: No

PubPeer comments:
 This article has an Editorial Expression of Concern: Expression of Concern to: Reprod Biol Endocrinol 15, 97 (2017) https: doi.org 10.1186 s12958-017-0316-8 The Editors-in-Chiefare issuing an Expression of Concern for this article [1]. After publication concerns were raised with respect to the specificity and validity of the placental Ang-(1u20137) levels assessed by Western blotting and reported in Fig. 4 because Ang-(1u20137), which is less than 1u2009kDa, was detected as a 34u2009kDa protein. All authors disagree with this Expression of Concern. , 
 Good reason for concern. The bands in the Ang-(1-7) Western blot appear to run in reverse and show possible manipulation. Molecular size of Ang-(1-7) is 899 Daltons, not 34,000 Daltons as identified in the figure and the peptide would migrate off the gel. The Ang-(1-7) antibody from Cloud Clone Corp (Wuhan China) appears non-specific. We previously showed that the Ang-(1-7) ELISA from Cloud Clone did not detect authentic Ang-(1-7), but measured non-specific immunoreactivity in human plasma that was abolished by plasma peptide extraction which would remove proteins such as that detected in the Ghadhanfar paper (Chappell et al; doi: 10.1161 HYPERTENSIONAHA.120.16724). Moreover, Western blots lack the sensitivity to detect fmol (pg) quantities of Ang-(1-7) and other angiotensin peptides in tissues. ![file] ,