Overview of the Renin-Angiotensin System

Angiotensin-Converting Enzyme 2 (ACE2) is an important component of the Renin-Angiotensin System which controls blood pressure but is now gaining recognition in the fields of virology and epidemiology for the role it plays in SARS-CoV-2 infection. By understanding the function of ACE2, we can better understand the role it may play in the seemingly unconnected symptoms of COVID-19.

You know when you go to the doctor, and they put your arm in that cuff and then squeeze it really tight to check and make sure your blood pressure is in a normal range? Well, turns out our bodies have a pretty great system for making sure that our blood pressure always stays in check as our diets change, we get stressed, or we inevitably forget to drink enough water… 

Inside our bodies, our good friends the liver and the kidney are hard at work making angiotensinogen – a peptide (or a short series of amino acids linked together) – and an enzyme called renin. Both are released into the bloodstream where renin cleaves off three amino acid subunits (or residues) from the end of angiotensinogen to make a new peptide called angiotensin 1. And, now seems like a good time to mention that this really cool “keep your blood pressure normal system” is really called the renin-angiotensin system (or sometimes the renin-angiotensin-aldosterone system). So, now that we’ve gotten our angiotensin 1 all ready to go, it’s time for this peptide to move along until it finds the ACE enzyme, or the Angiotensin-converting enzyme sticking out from the surface of a nearby cell. When angiotensin 1 bumps into ACE, the enzyme removes two more residues from the end of angiotensin 1, thus transforming this peptide into its close family member, angiotensin 2.

Now, here’s where the story takes a bit of a turn. So, angiotensin 1 was a fairly non-intrusive little peptide who mostly just exists to be turned into angiotensin 2. Angiotensin 2 on the other hand, plays a pretty important role in helping us regulate our blood pressure and fluid volume, but like some systems in our bodies, too much of a good thing can become a bad thing. If there is too much angiotensin 2, this causes our blood vessels to constrict which, in turn, increases our blood pressure. Angiotensin 2 also increases fluid retention, which also elevates our blood pressure. This excess fluid can actually cause the heart to grow which, as you can imagine, can lead to some pretty serious problems. If that wasn’t enough, angiotensin 2 can also cause inflammation and remodeling of our blood vessels which can lead to fibrosis or thickening of the tissue, and it can also have detrimental effects on the brain. So, how do we make sure we don’t tip the scales and have too much angiotensin 2 running rampant and causing all the bad stuff I just listed?

Well, one way to do this is to actually take a medication called an ACE inhibitor. You may have heard of this type of drug before, but now you know exactly why it’s such an important medication for someone who might be struggling with high blood pressure. ACE inhibitors come in and they block ACE from converting angiotensin 1 into angiotensin 2. I know this sounds bad because I told you that we actually need angiotensin 2 to regulate blood pressure, but don’t worry, we have lots of ACE enzymes and the drug doesn’t block all of them, it just helps ensure that we don’t overload our system with angiotensin 2, which then causes the bad stuff.

Our bodies also have what’s often referred to as a natural ACE inhibitor, which is none other than the Angiotensin-converting enzyme 2, or ACE2. The term “inhibitor” implies that ACE2 is doing what the drug would be doing, which is to stop the production of angiotensin 2. That isn’t really the case, so instead let’s call ACE2 an angiotensin 2 diverter. It basically takes the angiotensin 2 that ACE produces and breaks it down into a peptide that won’t raise our blood pressure. In fact, ACE2 turns angiotensin 2 into Angiotensin (1-7) which is actually a vasodilator, so it directly opposes the function of angiotensin 2. ACE2 was originally discovered within the context of heart disease and heart failure, and while it is critically important for preventing hypertension (or high blood pressure) and preserving our heart function, it turns out that this enzyme is also expressed across a wide range of tissues. ACE2 is found in organs, such as the lungs, gastrointestinal tract, skin, muscles, and kidneys, which indicates that it might play a broader role in other biological processes outside of blood pressure homeostasis. Many different research teams are looking into what other roles ACE2 might play in malnutrition, kidney diseases, diabetes, lung disease, and even viral infection, so this one little protein might actually help us better understand other pressing questions about human health and disease. 

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