Renin-angiotensin-aldosterone system

The main job of the cardiovascular system is to keep the blood moving, and to help facilitate that - blood pressure and more importantly 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 arterioles called the afferent arterioles.

After the afferent arteriole, 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's 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 arterioles which divide into capillaries a second time.

These capillaries are called peritubular 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 Henle - which has an ascending and a descending limb - and finally the distal convoluted tubule.

As filtrate 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 peritubular 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.

Okay - now if we zoom into the wall of the afferent arterioles, we’ll find a very special kind of smooth muscle cells, called juxtaglomerular cells, because they’re next to or “juxta” the glomerulus.

The main job of these cells is to always keep an eye open for signals that the blood pressure and or blood volume needs to rise.

These signals can come in three ways.

First, juxtaglomerular cells are mechanoreceptors also called the baroreceptors and they’re designed to mechanically feel if there’s low blood pressure in the incoming blood.

When they are stretched by an increased blood pressure they will inhibit renin release.

When they are collapsed from low blood pressure, they will stimulate renin release.

Second, juxtaglomerular 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 blood pressure coming out of the heart.

If they are stretched then the sympathetic nervous system will be downregulated, however if they collapse secondary to low blood pressure then the sympathetic nervous system is activated.

Specifically the Sympathetic nerves stimulate the b1 adrenergic receptors on the JG cells to stimulate renin.

The third signal for juxtaglomerular cells comes from specialized cells in the wall of the distal convoluted tubule called macula densa cells.

Macula densa 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 blood pressure rises, renal blood flow and, as consequence, glomerular filtration rate also increase.

This means that there’s more fluid and more dissolved sodium and chloride ions that reach the macula 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 juxtaglomerular cells in the afferent arteriole.

The major signal communicating between the Macula Densa and the Juxtaglomerular cells is prostaglandins especially PGE2.

As a result the use of NSAIDs (Nonsteroidal anti-inflammatory drugs) can block this signal and impair the response of the kidney to reduced blood pressure.

All three types of signals stimulate the juxtaglomerular cells to secrete renin and initiate the RAAS 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.

When they meet up, renin cleaves off a huge chunk of the angiotensinogen protein, leaving behind a tiny fragment called angiotensin I that’s just 10 amino acids long.