THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) - BIOLOGY - 2025

The renin-angiotensin-aldosterone system (RAAS for short) is a critical mechanism responsible for regulating blood volume and vascular system resistance.

It is composed of three main elements: renin, angiostensin II, and aldosterone. These act as a mechanism to raise blood pressure for a long time in low pressure situations. This is achieved by increasing sodium reabsorption, water reabsorption and vascular tone.

Source: Mikael Häggström, via Wikimedia Commons

The organs involved in the system are the kidneys, the lungs, the vascular system and the brain.

In cases where blood pressure drops, different systems act. In the short term, the response of the baroreceptors is observed, while the RAAS system is responsible for the response to chronic and long-term situations.

What is the RAAS?

The renin - angiotensin - aldosterone system is responsible for responding to adverse conditions of hypertension, heart failure and kidney related diseases.

Mechanism

Renin production

A series of stimuli, such as decreased blood pressure, beta activation, or activation by cells of the macula densa in response to a decrease in sodium load, cause certain specialized (juxtaglomerular) cells to secrete renin.

In the normal state, these cells secrete prorenin. However, after receiving the stimulus, the inactive form of prorenin is cleaved and becomes renin. The main source of renin is found in the kidney, where its expression is regulated by the mentioned cells.

According to studies in different species - from humans and dogs to fish - the renin gene has been highly conserved in the course of evolution. Its structure is similar to that of pepsinogen, a protease that, according to this evidence, could have a common origin.

Angiostetin I production

Once renin enters the bloodstream, it acts on its target: angiotensinogen. This molecule is produced by the liver and is constantly found in plasma. Renin acts by cleaving angiotensinogen into the molecule angiotensin I - which is physiologically inactive.

Specifically, renin in its active state cleaves a total of 10 amino acids located at the N-terminus of angiotensinogen, for the production of angiotensin. Note that in this system, the limiting factor is the amount of renin that exists in the bloodstream.

The gene that codes for human angiotensinogen is located on chromosome 1, while in the mouse it is on chromosome 8. Different homologues of this gene are present in different vertebrate lineages.

Angiotensin II production

The conversion of angiostensin I to II is mediated by an enzyme known as ACE (angiotensin converting enzyme). This is mainly found in the vascular endothelium of specific organs, such as the lungs and kidneys.

Angiotensin II has its effects on the kidney, adrenal cortex, arterioles, and brain by binding to specific receptors.

Although the function of these receptors has not been fully elucidated, it is suspected that they may participate in the production of vasodilation through the generation of nitric acid.

In plasma, angiotensin II has a half-life of only a few minutes, where it is cleaved by enzymes responsible for degrading peptides at angiotensin III and IV.

Action of angiotensin II

In the proximal tubule of the kidney, angiotensin II is responsible for increasing the exchange of sodium and H. This results in an increase in sodium reabsorption.

Increased levels of sodium in the body tend to increase the osmolarity of blood fluids, leading to a change in the volume of the blood. Thus, the blood pressure of the body in question is increased.

Angiotensin II also acts in the vasoconstriction of the arteriole system. In this system, the molecule binds to G protein-coupled receptors, triggering a cascade of secondary messengers that results in potent vasoconstriction. This system causes the increase in blood pressure.

Finally, angiotensin II also acts at the level of the brain, producing three main effects. First, the region of the hypothalamus is joined, where it stimulates the sensations of thirst, to increase the intake of water by the subject.

Second, it stimulates the release of the diuretic hormone. This results in an increase in water reabsorption, due to the insertion of aquaporin channels in the kidney.

Third, angiotensin decreases the sensitivity of the baroreceptors, decreasing the response to increased blood pressure.

Action of aldosterone

This molecule also acts at the level of the adrenal cortex, specifically in the zona glomerulosa. Here, the release of the hormone aldosterone is stimulated - a molecule of steroid nature that causes an increase in sodium reabsorption and potassium excretion in the distal tubules of the nephrons.

Aldosterone works by stimulating the insertion of luminal sodium channels and basolateral sodium potassium proteins. This mechanism leads to increased reabsorption of sodium.

This phenomenon follows the same logic as the one mentioned above: it leads to an increase in the osmolarity of the blood, increasing the patient's pressure. However, there are certain differences.

First, aldosterone is a steroid hormone and angiotensin II is not. As a result, it works by binding to receptors in the nucleus and altering the transcription of genes.

As such, the effects of aldosterone can take hours - or even days - to manifest, while angiostensin II acts quickly.

Clinical significance

The pathological functioning of this system can lead to the development of diseases such as hypertension - leading to increased blood circulation in inappropriate situations.

From a pharmacological perspective, the system is frequently manipulated in the management of heart failure, hypertension, diabetes mellitus, and heart attacks. Certain drugs, such as enalapril, losartan, spironolactone, work to decrease the effects of RAAS. Each compound has a particular mechanism of action.

References

1. Chappell, MC (2012). The Non-Classical Renin-Angiotensin System and Renal Function. Comprehensive Physiology, 2 (4), 2733.
2. Grobe, JL, Xu, D., & Sigmund, CD (2008). An intracellular renin-angiotensin system in neurons: fact, hypothesis, or fantasy. Physiology, 23 (4), 187-193.
3. Rastogi, SC (2007). Essentials of animal physiology. New Age International.
4. Sparks, MA, Crowley, SD, Gurley, SB, Mirotsou, M., & Coffman, TM (2014). Classical Renin-Angiotensin system in kidney physiology. Comprehensive Physiology, 4 (3), 1201-28.
5. Zhuo, JL, Ferrao, FM, Zheng, Y., & Li, XC (2013). New frontiers in the intrarenal renin-angiotensin system: a critical review of classical and new paradigms. Frontiers in endocrinology, 4, 166.