A healthy pregnancy outcome depends on the activation of the renin-angiotensin-aldosterone system (RAAS) as a regulated, integrated response to the growing demands of the conceptus. Both the circulating RAAS and the intrarenal renin-angiotensin system (iRAS) play major roles in cardiovascular function and fluid and electrolyte homeostasis. The circulating RAAS becomes dysfunctional in preeclampsia and we propose that dysregulation of the iRAS plays a role in development of the clinical syndrome known as preeclampsia. Experimental studies in animals have shown that placental renin, when released into the maternal circulation, can cause hypertension. We postulate that abnormal placental development is associated with over-secretion of renin and other RAS proteins/angiotensin (Ang) peptides by the placenta/decidua into the maternal circulation. We hypothesise that this is because of increased shedding of exosomes and other placental particles into the maternal circulation that not only contain RAS proteins and peptides but also microRNAs (miRNAs) that target RAS mRNAs, and Ang II type 1 receptor autoantibodies (AT1R-AAs), that are agonists for, and have the same actions as, Ang II. As a result, there is both suppression of the circulating RAAS that is responsible for maintaining maternal homeostasis and activation of the iRAS. Together with altered vascular reactivity to Ang peptides, the iRAS causes hypertension, renal damage and secondary changes in the neurohumoral control of the maternal circulation and fluid and electrolyte balance, which contribute to the pathophysiology of preeclampsia.

A dysfunctional endometrial renin–angiotensin system (RAS) could aid the growth and spread of endometrial cancer. To determine if the RAS is altered in endometrial cancer, we measured RAS gene expression and protein levels in 30 human formalin-fixed, paraffin-embedded (FFPE) endometrioid carcinomas and their adjacent endometrium. All components of the RAS were expressed in most tumours and in adjacent endometrium; mRNA levels of (pro)renin receptor (ATP6AP2), angiotensin II type 1 receptor (AGTR1), angiotensin-converting enzyme (ACE1) and angiotensin-converting enzyme 2 (ACE2) mRNA levels were greater in tumour tissue than adjacent non-cancerous endometrium (P = 0.023, 0.008, 0.004 and 0.046, respectively). Prorenin, ATP6AP2, AGTR1, AGTR2 and ACE2 proteins were abundantly expressed in both cancerous and adjacent non-cancerous endometrium. Staining was most intense in cancerous glandular epithelium. One potential target of the endometrial RAS, transforming growth factor beta-1 (TGFB1), which is essential for epithelial-to-mesenchymal transition, was also upregulated in endometrial cancer tissue (P = 0.001). Interestingly, TGFB1 was strongly correlated with RAS expression and was upregulated in tumour tissue. This study is the first to characterise the mRNA and protein expression of all RAS components in cancerous and adjacent non-cancerous endometrium. The greater expression of ATP6AP2, AGTR1 and ACE1, key elements of the pro-angiogenic/proliferative arm of the RAS, suggests that the RAS plays a role in the growth and spread of endometrial cancer. Therefore, existing drugs that inhibit the RAS and which are used to treat hypertension may have potential as treatments for endometrial cancer.

SARS‐CoV‐2 interacting with its receptor, angiotensin‐converting enzyme 2 (ACE2), turns the host response to viral infection into a dysregulated uncontrolled inflammatory response. This is because ACE2 limits the production of the peptide angiotensin II (Ang II) and SARS‐CoV‐2, through the destruction of ACE2, allows the uncontrolled production of Ang II. Recovery from trauma requires activation of both a tissue response to injury and activation of a whole‐body response to maintain tissue perfusion. Tissue and circulating renin‐angiotensin systems (RASs) play an essential role in the host response to infection and injury because of the actions of Ang II, mediated via its AT1 receptor. Both tissue and circulating arms of the renin angiotensin aldosterone system's (RAAS) response to injury need to be regulated. The effects of Ang II and the steroid hormone, aldosterone, on fluid and electrolyte homeostasis and on the circulation are controlled by elaborate feedback networks that respond to alterations in the composition and volume of fluids within the circulatory system. The role of Ang II in the tissue response to injury is however, controlled mainly by its metabolism and conversion to Ang‐(1‐7) by the enzyme ACE2. Ang‐(1‐7) has effects that are contrary to Ang II‐AT1R mediated effects. Thus, destruction of ACE2 by SARS‐CoV‐2 results in loss of control of the pro‐inflammatory actions of Ang II and tissue destruction. Therefore, it is the response of the host to SARS‐CoV‐2 that is responsible for the pathogenesis of COVID‐19.

Angiotensin-converting enzyme 2 (ACE2) is the receptor for COVID-19 (SARs-CoV-2). ACE2 protects the lung and heart from acute respiratory distress syndrome (ARDS) and acute myocarditis and arrhythmias, because it breaks down Angiotensin II, which has inflammatory effects in the lung and heart as well as in the kidney. When SARS-CoV-2 binds to ACE2, it suppresses it, so this protective action of ACE2 is lost. Death from COVID-19 is due to ARDS and also heart failure and acute cardiac injury. Drugs that prevent the inflammatory actions of Angiotensin II (i.e., Angiotensin receptor blockers, ARBs) prevent acute lung injury caused by SARS-CoV. Clinical trials are underway to test the risks and benefits of ARBs and angiotensin-converting enzyme inhibitors (ACEIs) in COVID-19 patients requiring hospitalization. Other potential treatments are also discussed.