Renin-angiotensin-aldosterone system

Definitions & Key takeaways

The renin-angiotensin-aldosterone system (RAAS) is a hormone system that plays a key role in regulating blood pressure and fluid balance in the body. It is composed of several hormones and enzymes that work together to regulate blood pressure by controlling the amount of fluid in the blood vessels.

Whenever there's a decrease in blood pressure as detected by the baroreceptors of the carotid sinus or aortic arch or the juxtaglomerular cells, the sympathetic nerves getting stimulated, or the macula densa cells sensing less sodium and chloride ions flowing through the tubules, kidneys secrete renin that converts angiotensinogen to angiotensin I, and then angiotensin-converting enzyme converts angiotensin I to angiotensin II.

Angiotensin II causes the efferent arteriole to constrict more than the afferent arteriole, which increases the glomerular filtration rate, it also causes the proximal tubule to reabsorb more sodium ions from the filtrate, increases thirst, and helps increase blood pressure, while it, also, stimulates the adrenal cortex to release aldosterone, which gets the kidneys to retain sodium and water, further raising blood pressure.

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Introduction0:00–1:53

The main job of the cardiovascular system is to keep the blood moving and to help facilitate that, BP and more importantly, blood volume is kept under tight control.
A major way the body does that is through a set of hormones that make up the renin angiotensin aldosterone system. But first things first, everything starts in the kidney.
Now within each kidney, blood from the renal artery flows into smaller and smaller arteries, eventually reaching the tiniest of arterials called the afferent arterials.
After the afferent arterial, blood moves into a tiny capillary bed called the glomerulus. The glomerulus is part of the functional unit of the kidney called the nephron.
There are about 1 million nephrons in each kidney, and each of them consists of a renal corpuscle made up of the glomerulus and the bowman's capsule surrounding it and a renal tubule.
The renal corpuscle is where blood filtration starts. Interestingly, once the blood leaves the glomerulus, it does not enter into venules.
Instead, the glomerulus funnels blood into efferent arterialles which divide into capillaries a second time. These capillaries are called paratubular capillaries because they are arranged around the renal tubule.
Now the renal tubule is made up of a proximal convoluted tubule, the nephron loop, also known as the loop of Henley, which has an ascending and descending limb, and finally the distal convoluted tubule.
As filtration makes its way through the renal tubule, waste and molecules like ions and water are exchanged between the tubule until finally urine is formed.
At the same time, the pertubular capillaries reunite to form larger and larger venous vessels. The veins follow the path of the arteries, but in reverse, so they keep uniting until they finally form the large renal vein which exits the kidney and drains into the inferior vena cava.
Alright, now if we zoom into the wall of the afferent arterialles, we'll find a very special kind of smooth muscle cell called juxtaglomerular cells because they're next to or juxta the glomerulus.

Juxtaglomerular cells1:53–4:18

The main job of these cells is to always keep an eye open for signals that the BP and or blood volume needs to rise. These signals can come in 3 ways.
First, juxta glomerular cells are mechanoreceptors, also called barrow receptors, and they're designed to mechanically feel if there's low BP in the incoming blood.
When they're stressed by an increased BP, they inhibit renin release. When they're collapsed from low BP, they stimulate renin release.
Second, juxaglomerular cells are supplied by sympathetic nerve fibers. The sympathetic nervous system is activated by mechanoreceptors stationed strategically in the aortic arch and carotid sinus to measure the immediate BP coming out of the heart.
If they're stretched, then the sympathetic nervous system will be down regulated. However, if they collapse secondary to low BP, then the sympathetic nervous system is activated.
Specifically, the sympathetic nerves stimulate the B1 adrenergic receptors and the JG cells to stimulate renin. The 3rd signal for juxaglomerular cells comes from specialized cells in the wall of the distal convoluted tubule called macula densa cells.
Vacula densis cells are chemoreceptors. That can sense when glomerular filtration rate increases or decreases based on the quantity of sodium and chloride ions flowing through the tubule.
Here's how it works. When BP rises, renal blood flow, and as a consequence, glomerular filtration rate also increases.
This means that there's more fluid and more dissolved sodium and chloride ions that reach the macular densa. Now if the opposite happens and there's decreased fluid and sodium and chloride ions getting to the macula densa cells, then that sends a signal to the juxaglomerular cells in the afferent arterial.
The major signal communicating between the macula densa and the juxaglomerular cells is prostaglandins, especially PGE2.
As a result, the use of NSAIDs or non-steroidal anti-inflammatory drugs can block this signal and impair the response of the kidney to reduce BP.
All three types of signals stimulate the juxta glomerular cells to secrete renin and initiate the renin angiotensin aldosterone system pathway.
Renin is an enzyme that gets into the plasma and looks for its primary substrate, angiotensinogen. Angiotensinogen is a large protein made up of over 400 amino acids that's produced by the liver and is always hanging out in the blood.

Renin-Angiotensinogen4:18–5:13

When they meet up, renin cleaves off a huge chunk of the angiotensinogen protein, leaving behind a tiny fragment called angiotensin 1, that's just 10 amino acids long, kind of like a tiny pearl found within a giant oyster.
Angiotensin one floats through the blood until it reaches various capillaries in the body. Now endothelial cells in general, but mostly those lining the vessels in the lungs, have an enzyme on their surface called angiotensin converting enzyme or ACE for short.
Angiotensin converting enzyme grabs angiotensin 1 and chops off two of its amino acids, leaving behind an 8 amino acid chain that's a really powerful hormone called angiotensin 2.
Angio means blood vessel and tensin means making everything more tense. So angiotensin 2 goes to the smooth muscles lining arterials all over the body that contain the angiotensin 2 receptor and causes them to tense up or contract, which leads to vasoconstriction of those blood vessels and increases resistance to blood flow.

Angiotensin II5:13–7:20

So angiotensin 2 travels through the blood and when it reaches the kidneys, it binds to angiotensin 2 receptors predominantly located along the efferent arterials.
Therefore, the afferent arterials are much more responsive to angiotensin 2 than the afferent arterials. So when there are low levels of angiotensin 2, only the efferent arterials constrict, and this makes less blood leave the glomerulus.
Or said differently, it makes more blood remain in the glomerulus, thereby increasing intraglomerular pressure and preserving the glomerular filtration rate.
However, when there are high levels of angiotensin 2, both the afferent and efferent arterials constrict, and this decreases both renal blood flow and glomerular filtration rate.
Angiotensin 2 also acts on the cells that line the proximal convoluted tubule, making them reabsorb more sodium ions from the filtrate.
And by the process of osmosis, water starts to follow the sodium ions. Angiotensin 2 also acts on the hypothalamus, which is at the base of the brain.
Where it stimulates thirst and increases the production of anti-diuretic hormone or ADH. ADH has its main effect on the cells lining the distal convoluted tubule and collecting duct, where it stimulates more aquaporins to get into the luminal surface of the cells.
Aquaporins make these cells more permeable to water, increasing water reabsorption. Ultimately, the increased thirst and water reabsorption increases the total circulating blood volume or blood flow, symbolized as Q.
In addition, the increased peripheral arterial resistance increases the total body resistance, symbolized as R. Since the change in BP P equals blood flow Q times resistance R, the BP rises.
But angiotensin 2's work isn't over yet. It also stimulates the adrenal glands, which are a pair of glands that sit on top of each kidney.

Aldosterone7:20–8:59

If we slice an adrenal gland open and zoom in, we'll see that it's made up of two parts, an inner medulla and an outer cortex.
The cortex is further subdivided into three more layers the zonaglomerulosa, the zona fascicuata, and the zona reticularis.
Angiotensin 2 stimulates cells in the outermost layer, the zonaglomerulosa, to secrete aldosterone. Aldosterone belongs to a class of steroids or lipid soluble hormones called mineral corticoids which help regulate the sodium balance of the body.
Aldosterone does that by acting on the cells that line the distal tubules and collecting ducts. Aldosterone gets into those cells and binds its receptor, forming an aldosterone receptor complex.
This complex is able to control the expression of genes, increasing levels of some proteins over others. One protein that gets expressed a lot is the sodium potassium ATPase ion pump, which sits on the basilateral surface of the cells.
These pumps push sodium into the blood and pull potassium into the cells. Ultimately this helps drive a concentration gradient that pulls sodium and water out of the lumen of the tubule and into the blood and secrete potassium.
In fact, most patients with intense activation of the renin angiotensin aldosterone system can be profoundly hypokalemic, as before, this helps to boost the BP.
Keep in mind though that this process can take several hours or even days, so it's considered a late response of the renin angiotensin aldosterone system.

Review8:59–9:48

Alright, as a quick recap, whenever there's a decrease in BP as detected by the barrow receptors of the carotid sinus or aortic arch or the juxaglomerular cells, the sympathetic nerves getting stimulated, or the macular denser cells sensing less sodium and chloride ions flowing through the tubules, kidneys secrete renin that converts angiotensinogen to angiotensin 1, and then angiotensin converting enzyme converts angiotensin 1 to angiotensin 2.
Angiotensin 2 causes the efferent arterial to constrict more than the afferent arterial, which increases the glomerular filtration rate.
It also causes the proximal tubule to reabsorb more sodium ions from the filtrate, increases thirst, and helps increase BP, while it also stimulates the adrenal cortex to release aldosterone, which gets the kidneys to retain sodium in water.