RENIN: STRUCTURE, PRODUCTION, SECRETION, FUNCTIONS - BIOLOGY - 2024

The renin, also known as angiotensinogenasa, is an aspartyl protease that has important implications in electrolyte homeostasis and control of blood pressure in mammals.

This protein is secreted from the kidney into the bloodstream and is responsible for the increase in blood pressure in experimental animals when kidney extracts are injected.

Representative schematic of the Renin-Angiotensin system in the human body (Source: Mikael Häggström via Wikimedia Commons)

As it is a substance produced by a tissue and secreted into the circulation with a target far from its production site, renin is considered a hormone.

The hormones can be proteins or polypeptides, have a steroidal origin or derived from the amino acid tyrosine. Renin is a protein hormone in nature and its catalytic action involves the enzymatic cleavage of other proteins (it is a protease).

This hormone was discovered in the late 1890s. However, it was not until the late 1990s that its physiological origin and molecular structure were accurately determined.

Structure

Human renin is a glycoprotein with enzymatic activity and a molecular weight of just over 37 kDa. The molecule is made up of two domains separated by a deep cleft within which its active site is located.

Both domains of renin are similar in sequence and are composed mainly of β-folded sheets.

Different analyzes of the sequence of this protein reveal that it has more than 30 basic amino acid residues, including various arginines, lysines and histidines.

Furthermore, it is known that hydrophobic centers and large hydrophilic surfaces are found throughout the structure that provide stability to the protein in different contexts.

The active site of the enzyme is located in the cleft formed by the two domains and the essential amino acids for catalysis are two aspartic acid residues at positions 38 and 226, which is why this is an "aspartyl" protease.

Production

Renin is produced in the juxtaglomerular apparatus of the kidney, a specialized structure found at the site of contact between the distal convoluted tubule and its glomerulus of origin.

This apparatus consists of three components: the granule cells, the extraglomerular mesangial cells, and the macula densa.

Dense macula

The macula densa is formed by a row of closely knit cubic epithelial cells that line the tube at the site of contact with the glomerulus and is considered the start of the distal convoluted tubule.

Mesangial cells

The extraglomerular mesangial cells are found forming a triangular region between the afferent arteriole, the efferent arteriole and the macula densa, they are considered an extension of the glomerular mesangial cells. They are also called agranular cells.

Granular cells

The granule cells are called juxtaglomerular cells and are located in the walls of the afferent and efferent arterioles and in the area of ​​the extraglomerular mesangial cells.

These granule cells are called by the presence of secretory granules in their cytoplasm. Granules containing renin, as well as a renin precursor, pro-renin, which is formed from pre-pro-renin.

Pre-pro-renin is a prehormone that has 406 amino acids in humans. This prehormone undergoes a post-translational proteolytic cleavage, thus losing a sequence of 23 residues at its amino terminal end.

Cleavage of pre-pro-renin converts it to pro-renin, 383 amino acids long. The subsequent cleavage of another sequence at the N-terminus of pro-renin is what directs the formation of renin, an active 340 amino acid protease.

Both pro-renin and renin can be secreted into the circulation, but very little pro-renin is converted to active renin in this connective tissue. The enzymes responsible for the conversion of pro-renin to renin are known as kallikreins and cathepsins.

Once renin is secreted into the circulation, it has a half-life of no more than 80 minutes and secretion is highly regulated.

In addition to the kidney, renin can be produced by other tissues or organs such as the testes, ovaries, arteriole walls, adrenal cortex, pituitary, brain, amniotic fluid, and others.

Although applicable to many animals, studies involving removal of the kidneys show that circulating renin activity drops dramatically to levels very close to zero.

Secretion

Renin secretion is increased by a series of stimuli that appear when the volume of the extracellular fluid decreases, when arterial pressure decreases or when sympathetic activity in the renal nerves increases.

Several factors related to the regulation of renin secretion have been described:

- The renal perfusion pressure detected by the baroreceptors (stretch receptors) of the afferent arteriole

- Changes in the volume and composition of the fluid that reaches the macula densa

- Activity of the renal sympathetic nerves

- Prostaglandins

- Atrial natriuretic peptide.

The baroreceptor mechanism of the afferent arteriole causes a decrease in renin secretion when there is an increase in the pressure of the afferent arteriole at the level of the juxtaglomerular apparatus. Its secretion increases when the baroreceptor activity decreases as the pressure falls.

Another sensor related to the regulation of renin secretion is found in the macula densa. The higher the Na + and Cl- reabsorption rate and the concentration of these electrolytes in the fluid that reaches the macula densa, the lower the renin secretion and vice versa.

Increased activity of renal sympathetic nerves, as well as of circulating catecholamines through norepinephrine released at sympathetic endings in juxtaglomerular cells, increases renin secretion.

Prostaglandins, specifically prostacyclins, stimulate renin secretion by direct effect on the granule cells of the juxtaglomerular apparatus.

Angiotensin II, through a negative feedback effect, inhibits renin secretion by direct effect on granule cells. Another hormone such as vasopressin inhibits renin secretion.

Atrial natriuretic peptide (ANP), which is produced in the heart atrial muscle, inhibits renin secretion.

The combined effect of all the stimulatory and inhibitory factors is what determines the rate of renin secretion. Renin is secreted into the renal blood and then leaves the kidneys to circulate throughout the body. However, a small amount of renin remains in the kidney fluids.

Features

Renin is an enzyme that itself does not have vasoactive functions. The only known function of renin is to cut angiotensinogen at the amino terminus, generating a decapeptide called Angiotensin I.

Angiotensinogen is a glycoprotein from the group of α2 globulins synthesized by the liver and is present in circulating blood.

Since angiotensin I has very poor vasopressor activity and it must be processed "downstream" by another protease, renin participates in the initial steps of blood pressure regulation, in a system known as renin-angiotensin.

Angiotensin II has a very short half-life (between 1 and 2 minutes). It is rapidly metabolized by various peptidases that fragment it and some of these fragments, such as Angiotensin III, retain some vasopressor activity.

The general functions of the renin -angiotensin system are multiple and can be summarized as follows:

- Arteriolar constriction and increase in systolic and diastolic pressure. Angiotensin II is four to eight times more potent than norepinephrine for this function.

- Increased secretion of aldosterone due to the direct effect of Angiotensin II on the adrenal cortex. The renin-angiotensin system is the main regulator of aldosterone secretion.

- Facilitates the secretion of norepinephrine by direct effect on post-ganglionic sympathetic neurons.

- It influences the contraction of mesangial cells, which decreases the glomerular filtration rate and, due to a direct effect on the renal tubules, increases sodium reabsorption.

- At the brain level, this system reduces the sensitivity of the baroreceptor reflex, which enhances the vasopressor effect of Angiotensin II.

- Angiotensin II stimulates water intake by promoting the mechanisms of thirst. It increases the secretion of vasopressin and the hormone ACTH.

Related pathologies

The renin-angiotensin system therefore has an important role in hypertensive pathologies, especially those of renal origin.

Thus, the constriction of one of the renal arteries generates sustained hypertension that can be reversed if the ischemic (defective) kidney is removed or the renal arterial constriction is released in time.

An increase in renin production is generally associated with unilateral constriction of the renal artery connecting one of the kidneys, resulting in hypertension. This clinical condition may be due to congenital defects or other renal circulation abnormalities.

The pharmacological manipulation of this system, in addition to the use of angiotensin II receptor blockers, are the fundamental tools for the treatment of arterial hypertension.

High blood pressure is a silent and progressive disease that affects a large part of the world's population, especially adults over 50 years of age.

References

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