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Renin-Angiotensin System
Written by Tim Sheppard MBBS BSc. Last updated 17/4/10

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What is the renin-angiotensin system?

The body is absolutely brilliant. It's actually REALLY clever, and it's beautifully designed to cope with so much that the world can throw at it. A lot of the processes which go on are designed to keep everything in a happy balance, and this is generally known as homeostasis. One of the things which needs to be kept in a happy balance is blood pressure - the pressure in the circulatory system, or the pressure that the blood is being kept at.

One of the ways which it manages to control blood pressure is the renin-angiotensin system (or the renin-angiotensin-aldosterone system). In fact, there's a whole range of names for it, but it basically means a clever pathway that exists in the body to cause the blood pressure to stay right. And, rather unsurprisingly, it involves chemicals called renin and angiotensin.

It starts in the kidneys. The kidneys are really well placed to detect what the blood pressure is like, because they're in a place that is always well supplied with blood. The kidneys are filters for the blood, getting rid of all the rubbish that the body doesn't like. Although the supply of the kidneys isn't the same as the lungs or the portal circulation, they still get around 20% of the blood which that heart pumps out.

The kidneys are made up of lots and lots of copies of the same component part. It's a bit like a whole load of pipes, feeding into the ureter which is a single pipe leading to the bladder. So each of these individual pipes filters the blood, and each pipe is made up of different key features. One of these features is the glomerulus, and next to the glomerulus is the juxtaglomerular apparatus (JGA). It's this JGA that senses the blood pressure and decides, if it's too low, to throw some renin out into the blood stream.

When renin is thrown out into the blood stream, it turns angiotensinogen (found in the liver) into angiotensin I (Ang I). That's all well and good and it means that we've got more angiotensin I kicking about; why is that important? Well, quite simply, if you've got more angiotensin I then you'll end up with more angiotensin II (Ang II), because angiotensin converting enzyme (ACE) happily converts the one into the other. ACE is a really important enzyme, because Ang II is a chemical which causes vasoconstriction. So, if ACE is working properly, then it'll cause the production of Ang II, and hence it will lead to an awful lot of vasoconstriction.

That's a pretty impressive system, and if you're anything like me, you'd be quite happy if it stopped there - it seems to work, and what is more, it saves you from having to learn anymore! However, when you think about it, that's not necessarily the best place for it to end. If you're loosing blood, then it's all very well causing vasoconstriction, but eventually you'll reach a point where that's just not going to help any more. So what can you do? Well, rather helpfully, Ang II has a number of functions in addition to what we've just thought about which work to increase the amount of water in the blood. One of them is ADH secretion, and another is the synthesis of aldosterone.

As with a lot of things relating to blood pressure, the function of aldosterone is primarily in the kidneys. The main place it acts, when we're thinking about blood pressure regulation, is at the distal tubule. Here it acts on receptors, which increase how much potassium and sodium can cross the membranes. They also activate pumps which pump sodium from the urine back into the blood (where it originally came from). Whenever sodium is pumped from one side of a membrane to another, it creates an osmotic gradient. This is a complicated concept, but put most simply, the sodium going from point A to point B effectively "pulls" water with it, so water ends up travelling (by osmosis) in the same direction as the sodium.

ADH is a hormone that is thrown into the blood stream by a part of the body called the pituitary gland which you'll find up by your brain. There's two parts to it - the anterior pituitary and the posterior pituitary. It's from the posterior pituitary that ADH is secreted. This works in a different way to aldosterone, but importantly it has a similar function: it works in the kidney to increase the amount of water that is pulled back into the blood stream.

The reason this is more useful than just vasoconstriction is that the blood volume is increased when water is added to it. The obvious effect is on maintaining blood pressure, but in many instances this will be more helpful than simply causing vasoconstriction - and if there's blood loss, it's better to try and replace the fluid than to try and squeeze the arteries until there's no squeezing left to be done!!

If all the blood vessels - and particularly the arterioles - are tightening up, and if the kidneys are re-absorbing water into the blood, then the pressure in the circulatory system is markedly increased, and this means that the blood pressure is going to be raised. So the kidneys, which initially did their bit by throwing out renin in response to low blood pressure, have successfully caused the body to get the balance back to normal. With everything back in balance, the JGA stops secreting renin (this may seem odd because you'd imagine that vasoconstriction would reduce the amount of blood getting to the JGA, but it does make sense).

What is renin?

Renin is a protein hormone which is released by the kidney in order to control blood pressure. This means that it's a chemical which the kidney releases that acts elsewhere in the body to try and get the blood pressure at the right level.

Renin is actually an enzyme that acts on angiotensinogen (which is why it's sometimes called angiotensinogenase). This means that although it acts elsewhere in the body, it doesn't have a cellular target, but its aim is to make a difference to the angiotensinogen.

There are a number of ways that it can do this. The normal soluble renin which is thrown out into the circulatory system happily converts the precursor into angiotensin I. However, renin can also bind to receptors that make the enzyme work four times as well!

What is angiotensin?

Angiotensin is actually the name given to a number of proteins which work in the blood system to increase blood pressure, but with the most important one being angiotensin II. The name of the protein pretty much gives it away: angio- (meaning something to do with a vessel - especially a blood vessel) and -tensin (which makes you think of something tense, or tight).

As is made quite clear from the explanation of the renin-angiotensin system, angiotensin actually starts out as angiotensinogen, which is what scientists call a precursor - it is a big protein which doesn't actually do anything interesting until it is turned into something else.

That thing which it is turned into is angiotensin I, happily so-called because it is the first in the sequence of angiotensins. Angiotensin I is not impotent, but it's not a particularly interesting chemical because it isn't the most interesting thing in the world. What's important is that angiotensinogen is turned into angiotensin I by renin.

Once we've got angiotensin I floating around the blood system, we get angiotensin II being produced, because there is angiotensin converting enzyme on the lining of most blood vessels. Because there's a huge number of capillaries working their way densely through the lungs, most of the conversion happens here.

The lesser-known descendants of angiotensin II are angiotensin III and angiotensin IV. These are smaller proteins than angiotensin II, because even more has been cut off the end of the protein. They do cause some vasoconstriction, but nothing that you'd really want to write home about. They're just one of those things we don't pay much attention to because it doesn't look like they're that important.

The actions of angiotensin II are made clearer in the explanation of the renin-angiotensin system. The important thing to come away with is that it causes the blood pressure to go up, which makes it an immensely useful chemical when you're body is worried about blood pressure.

What is angiotensin converting enzyme (ACE)?

Well, clearly angiotensin converting enzyme is an enzyme but what does it do? Angiotensin converting enzyme is an enzyme which converts the angiotensins - that is, it converts angiotensin I into angiotensin II. It's obviously a key part of the renin-angiotensin system, because without this you won't be able to produce all of the fantastic effects that angiotensin II has. In fact, this particular enzyme has a special importance. As well as playing a key role in getting from secretion of renin to production of angiotensin II, this enzyme is an important target for drugs.

The enzyme is found on the edge of blood vessels, mainly capillaries, but because there's loads of capillaries packed densely (i.e. really tightly) into the lungs, most of the conversation of angiotensin I into angiotensin II happens here.

What is aldosterone?

Aldosterone is a steroid hormone that's made in the outside part of the adrenal gland (which is just above the kidney). The adrenal gland has an inner part (the medulla) and an outside part (the cortex), and it's the outer part of the cortex (the zona glomerulosa) which is used to make aldosterone. Because it's a steroid hormone, it means that it's made out of cholesterol, and it fits into the mineralocorticoid family because it effects the way that the body deals with water and salt. In fact, aldosterone is like the grandfather of the mineralocoritcoid family - anything which is similar to aldosterone is considered a mineralocorticoid.

Of course, none of that tells you anything remotely interesting about what aldosterone does. Happily, aldosterone is not a dull hormone - there are a number of key things which it does once it's been thrown into the blood stream, basically acting to control what happens in the kidney.

One of the ways that it does this is by activating proteins in the distal tubule that swap sodium with potassium (i.e. more sodium is taken back into the blood, and more potassium is sent into the urine). The other thing it does is control the amount of hydrogen ions which are secreted into the urine from the collecting duct part. This is important for regulating the acidity of blood.

Aldosterone is secreted as a response to levels of angiotensin II, adrenocorticotrophic hormone (ACTH) or potassium. It's also produced when the atria of the heart aren't stretched as much as normal.

Why does the juxtaglomerular apparatus stop secreting renin?

This is a very good question. When the body has low blood pressure, there's less blood getting to the kidneys so that juxtaglomerular apparatus sends out renin into the system. This increases the blood pressure by causing vasoconstriction. But if this is causing the blood vessels to get tighter, doesn't this mean even less blood gets to the kidneys and even more renin gets sent out?

Well, actually: no - but to understand this you need to think about the way that blood gets to and from the glomerulus. Blood gets to the glomerulus in the afferent arteriole, and gets away from the glomerulus in the efferent arteriole. The JGA is between these two, sensing the blood pressure in between and deciding whether or not it is high enough for the kidneys to work. If it isn't, it releases renin. This renin causes the production of angiotensin II (the cause of the vasoconstriction).

Here is the key part: angiotensin II acts mainly on the efferent arteriole. This means that the blood coming towards the JGA isn't as affected as the blood leaving the JGA. If the arteriole going away from the JGA gets tighter, the pressure will be backed up to the glomerulus and the JGA will decide that actually the pressure is fine - and it can stop releasing renin.

How do drugs affect the renin-angiotensin system?

The reason this is such an important question is that medications used to control blood pressure often involve the renin-angiotensin system. This, of course, makes lots of sense - if the system causes the blood pressure to rise, then blocking it is a good way to keep blood pressure down.

ACE-inhibitors are medications designed to block the angiotensin converting enzyme from converting angiotensin I to angiotensin II. If you have less angiotensin II around, then the body will be thwarted in its attempts to raise blood pressure. Preventing the production of angiotensin II prevents it from causing vasoconstriction, keeping the blood pressure low.

Angiotensin II receptor blockers work in a similar way. They are antagonists to the angiotensin II receptor, which means they block angiotensin II from working. If angiotensin II is being produced but not working, then it won't be able to cause vasoconstriction, so it won't be able to increased blood pressure.

One of the problems of this method of controlling blood pressure is when you have renal artery stenosis. In that situation, you don't want to be messing around with the renin-angiotensin system because it's the only way that the kidneys are kept safe. As explained above, the juxtaglomerular apparatus secretes renin when the blood pressure in the glomerulus is low. In renal artery stenosis, there's less blood getting to the glomerulus, and so it will be low. By secreting renin, the pressure in the glomerulus is kept high, and the kidneys keep working. If you block the renin-angiotensin system so that this safety mechanisms is removed, then all of the kidney's efforts to keep the pressure high in the glomerulus will be ruined, and the kidney will eventually die. If someone has renal artery stenosis on both sides (i.e. bilateral), they shouldn't be taking these medications.

Another important drug to affect this system is spironolactone. This acts by blocking aldosterone, so the pump in the distal tubule doesn't swap potassium for sodium and there's less water being reabsorbed into the blood. This is good for preventing the blood pressure getting high, but because less potassium is being removed from the blood, it can lead to potassium levels getting too high, which can be dangerous. Not everyone gets this, but it's something that is important to remember.

Further Reading