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In times of coronavirus disease 2019 (COVID-19), the impact of severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 infection on pregnancy is still unclear. The presence of angiotensin-converting enzyme (ACE) 2 (ACE2), the main receptor for SARS-CoV-2, in human placentas indicates that this organ can be vulnerable for viral infection during pregnancy. However, for this to happen, additional molecular processes are critical to allow viral entry in cells, its replication and disease manifestation, particularly in the placenta and/or feto–maternal circulation. Beyond the risk of vertical transmission, COVID-19 is also proposed to deplete ACE2 protein and its biological actions in the placenta. It is postulated that such effects may impair essential processes during placentation and maternal hemodynamic adaptations in COVID-19 pregnancy, features also observed in several disorders of pregnancy. This review gathers information indicating risks and protective features related to ACE2 changes in COVID-19 pregnancies. First, we describe the mechanisms of SARS-CoV-2 infection having ACE2 as a main entry door and current evidence of viral infection in the placenta. Further, we discuss the central role of ACE2 in physiological systems such as the renin–angiotensin system (RAS) and the kallikrein–kinin system (KKS), both active during placentation and hemodynamic adaptations of pregnancy. Significant knowledge gaps are also identified and should be urgently filled to better understand the fate of ACE2 in COVID-19 pregnancies and the potential associated risks. Emerging knowledge will be able to improve the early stratification of high-risk pregnancies with COVID-19 exposure as well as to guide better management and follow-up of these mothers and their children.

The kidney is an important target of the renin‐ ANG ‐aldosterone system ( RAAS ). To date, several studies have demonstrated the existence of a local RAAS in various tissues, including the renal tissue. The mineralocorticoid aldosterone is known to play a critical role in the classical RAAS ; however, its effect on mesangial cells ( MC s) remains to be elucidated. Based on this, our aim was to investigate whether aldosterone stimulation can modulate the intracellular RAAS of immortalized human MC s by evaluating ANG ‐converting enzyme ( ACE )/ ANG II / ANG II receptor type 1 ( AT 1) and ANG ‐converting enzyme 2 ( ACE 2)/ ANG (1‐7)/ MAS receptor axes. To realise this, protein expression, enzyme activity, and immunofluorescence were performed under aldosterone stimulation and in the presence of the mineralocorticoid receptor ( MR ) antagonist spironolactone ( SPI ). We observed that high doses of aldosterone increase ACE activity. The effect of aldosterone on the catalytic activity of ACE was completely abolished with the pretreatment of SPI suggesting that the aldosterone‐induced cell injuries through ANG II release were attenuated. Aldosterone treatment also decreased the expression of MAS receptor, but did not alter the expression or the catalytic activity of ACE 2 and ANG (1‐7) levels. Spironolactone modulated the localization of ANG II and AT 1 receptor and decreased ANG (1‐7) and MAS receptor levels. Our data suggest that both aldosterone and the MR receptor antagonist can modulate both of these axes and that spironolactone can protect MC s from the damage induced by aldosterone.

Mesangial cells (MCs) are a local target for aldosterone (aldo) action in the modulation of the renin angiotensin aldosterone system (RAAS).Its molecular mechanisms is far from clear, and are extremely important in understanding renal pathologies. We investigated if the effect of aldosterone stimulus in supra, physiological and sub physiological doses was able to modulate the intracrine human MCs RAAS. We performed viability assays, western blot, immunofluorescence, ACE and ACE2 activities. As a result, we have obtained that the ACE activity was increased after MCs treatment with aldosterone 1 and 10 nM when compared with 0.1nM after 72h. Previous cells treatment with spirolactone followed by aldo reduced ACE catalytic activity but not ACE2. ACE and ACE 2 expression increased after 72h of MCs treatment with aldo 10 nM. The immunofluorescence showed that ACE was overexpressed in MCs after 72h with 10nM aldosterone treatment being similar to control group, differing from the treatment with spirolactone + aldo stimulation that decreased ACE expression, internalized Angiotensin II and changed the AT1 receptor localization. The same treatment increased MAS receptor production in MCs after 72h of aldosterone treatment with 10, 1.0, 0.1 and 0.01nM , but not with spirolactone + aldo treatment that inhibited receptor synthesis. ACE2 was detected in cell nucleus with 24h of treatment with aldo and in cytoplasm after 72h, being reduced after the treatment with spirolactone+aldo. Ang 1-7 was localized at cell nucleus and in cytoplasm after treatment with aldo 24h and 72h, decreasing with spirolactone + aldo treatment. Immunofluorescence results demonstrated that MCs pre-treated with spironolactone decreased ACE, ACE2 and MAS receptor expression, and altered ANG II localization, suggesting that spironolactone acts on the mineralocorticoid receptor internalizing ANG II into the nucleus, probably by AT1 and AT2 receptors pathways. These results demonstrated that aldosterone can modulate the local RAAS in mesangial cells suggesting that its physiological concentrations are necessary for the feasibility of these cells while high doses are cytotoxic and altered the local system.

Aldosterone (Aldo) and glucocorticoids are steroid hormones reported to induce several responses in human mesangial cells (MC), essential cells for the maintenance of glomerular structure and filtration. Alterations in these cells may result in numerous diseases such as hypertension, diabetes and lupus nephritis. Renin Angiotensin-Aldosterone System (RAAS) was reported to have a role in physiological functions such as modulate differentiation, proliferation and apoptosis. Since MC have a relevant role for the maintenance of a health glomerular environment and the catalytic activity of RAAS enzymes are fundamental for biologically active peptides generation, we decided to study the effects of aldosterone and dexamethasone (Dexa) in the modulation of RAAS enzymes activities and how these modulations may influence in MC behaviour. Cell viability assay showed that after 24h of spironolactone (SPI) stimulus MC viability increased in comparison to control cells, as well as the combination of SPI+Aldo. When only aldosterone was added as stimulus, alterations in viability were not found. Dexa treatment also increased cell viability, but the following combination Aldo+Dexa, SPI+Dexa and SPI+Aldo+Dexa did not result in viability alterations which may indicate that dexamethasone needs to binding Aldo receptor to increase MC viability. ACE catalytic activity decreased in MC medium when these cells were exposed to Dexa and Aldo+Dexa for 4h and compared to positive control (Angiotensin II; Ang II) and SPI. After 24h, MC lysates exposed to Aldo showed an increase in ACE activity in relation to Ang II and Aldo+Dexa which, may indicate a protective effect of dexamethasone against the deleterious effects of aldosterone. ACE 2 activity increased in MC lysates exposed to SPI for 24h in comparison to control cells. Immunofluorescence assay demonstrated alteration in collagen type IV (CIV) expression. SPI treatment increased CIV expression in comparison to all groups while Aldo+Dexa showed a decrease in CIV expression compared to control cells. Isolated stimulus with Aldo or Dexa demonstrated similar stain pattern with control. To date, we can conclude that steroids hormones induce modulations in ACE and ACE 2 activity and in CIV expression.