Renin

Renin (etymology and pronunciation), also known as an angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin aldosterone system (RAAS)—also known as the renin-angiotensin-aldosterone axis—that mediates extracellular volume (i.e., that of the blood plasma, lymph and interstitial fluid), and arterial vasoconstriction. Thus, it regulates the body's mean arterial blood pressure.

Renin is often improperly referred to as a hormone even though it has no peripheral receptors and rather has an enzymatic activity with which it hydrolyzes angiotensinogen to angiotensin I.

Biochemistry and physiology

Structure

The primary structure of renin precursor consists of 406 amino acids with a pre- and a pro-segment carrying 20 and 46 amino acids, respectively. Mature renin contains 340 amino acids and has a mass of 37 kDa.^[1]

Secretion

The enzyme renin is secreted by the afferent arterioles of the kidney from specialized cells of the juxtaglomerular apparatus – the juxtaglomerular cells, in response to three stimuli:

1. A decrease in arterial blood pressure (that could be related to a decrease in blood volume) as detected by baroreceptors (pressure-sensitive cells). This is the most direct causal link between blood pressure and renin secretion (the other two methods operate via longer pathways).
2. A decrease in sodium levels in the ultrafiltrate of the nephron. This flow is measured by the macula densa of the juxtaglomerular apparatus.
3. Sympathetic nervous system activity, which also controls blood pressure, acting through the beta₁ adrenergic receptors.

Human renin is secreted by at least 2 cellular pathways: a constitutive pathway for the secretion of the precursor prorenin and a regulated pathway for the secretion of mature renin.^[2]

Renin-angiotensin system

The renin-angiotensin system, showing role of renin at bottom.^[3]

The renin enzyme circulates in the blood stream and breaks down (hydrolyzes) angiotensinogen secreted from the liver into the peptide angiotensin I.

Angiotensin I is further cleaved in the lungs by endothelial-bound angiotensin-converting enzyme (ACE) into angiotensin II, the most vasoactive peptide.^[4][5] Angiotensin II is a potent constrictor of all blood vessels. It acts on the smooth muscle and, therefore, raises the resistance posed by these arteries to the heart. The heart, trying to overcome this increase in its 'load', works more vigorously, causing the blood pressure to rise. Angiotensin II also acts on the adrenal glands and releases aldosterone, which stimulates the epithelial cells in the distal tubule and collecting ducts of the kidneys to increase re-absorption of sodium, exchanging with potassium to maintain electrochemical neutrality, and water, leading to raised blood volume and raised blood pressure. The RAS also acts on the CNS to increase water intake by stimulating thirst, as well as conserving blood volume, by reducing urinary loss through the secretion of vasopressin from the posterior pituitary gland.

The normal concentration of renin in adult human plasma is 1.98-24.6 ng/L in the upright position.^[6]

Function

Renin activates the renin-angiotensin system by cleaving angiotensinogen, produced by the liver, to yield angiotensin I, which is further converted into angiotensin II by ACE, the angiotensin-converting enzyme primarily within the capillaries of the lungs. Angiotensin II then constricts blood vessels, increases the secretion of ADH and aldosterone, and stimulates the hypothalamus to activate the thirst reflex, each leading to an increase in blood pressure. Renin's primary function is therefore to eventually cause an increase in blood pressure, leading to restoration of perfusion pressure in the kidneys.

Renin is secreted from juxtaglomerular kidney cells, which sense changes in renal perfusion pressure, via stretch receptors in the vascular walls. The juxtaglomerular cells are also stimulated to release renin by signaling from the macula densa. The macula densa sense changes in volume delivery to the distal tubule, and responds to a drop in tubular volume by stimulating renin release in the juxtaglomerular cells. Together, the macula densa and juxtaglomerular cells comprise the juxtaglomerular complex.

Renin secretion is also stimulated by sympathetic nervous stimulation, mainly through beta-1 adrenoceptor activation.

Renin can bind to ATP6AP2, which results in a fourfold increase in the conversion of angiotensinogen to angiotensin I over that shown by soluble renin. In addition, renin binding results in phosphorylation of serine and tyrosine residues of ATP6AP2.^[7]

The level of renin mRNA appears to be modulated by the binding of HADHB, HuR and CP1 to a regulatory region in the 3' UTR.^[8]

Genetics

The gene for renin, REN, spans 12 kb of DNA and contains 8 introns.^[9] It produces several mRNA that encode different REN isoforms.

Mutations in the REN gene can be inherited, and are a cause of a rare inherited kidney disease. This disease is autosomal dominant, meaning that it is characterized by a 50% chance of inheritance and is a slowly progressive chronic kidney disease that leads to the need for dialysis or kidney transplantation. Many – but not all – patients and families with this disease suffer from an elevation in serum potassium and unexplained anemia relatively early in life. Patients with a mutation in this gene can have a variable rate of loss of kidney function, with some individuals going on dialysis in their 40's while others may not go on dialysis until into their 70’s. This is a rare inherited kidney disease that exists in less than 1% of people with kidney disease.^[10]

Model organisms

Model organisms have been used in the study of REN function. A knockout mouse line, called Ren1^{Ren-1c Enhancer KO} was generated.^[16] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.^[14][17] Twenty four tests were carried out on mutant mice and two significant abnormalities were observed. Homozygous mutant animals had a decreased heart rate and an increased susceptibility to bacterial infection.^[14] A more detailed analysis of this line indicated plasma creatinine was also increased and males had lower mean arterial pressure than controls.^[16]

Clinical applications

An over-active renin-angiotension system leads to vasoconstriction and retention of sodium and water. These effects lead to hypertension. Therefore, renin inhibitors can be used for the treatment of hypertension.^[18][19] This is measured by the plasma renin activity (PRA).

In current medical practice, the renin-angiotensin-aldosterone-System's overactivity (and resultant hypertension) is more commonly reduced using either ACE inhibitors (such as ramipril and perindopril) or angiotensin II receptor blockers (ARBs, such as losartan, irbesartan or candesartan) rather than a direct oral renin inhibitor. ACE inhibitors or ARBs are also part of the standard treatment after a heart attack.

The differential diagnosis of kidney cancer in a young patient with hypertension includes juxtaglomerular cell tumor (reninoma), Wilms' tumor, and renal cell carcinoma, all of which may produce renin.^[20]

Measurement

Renin is usually measured as the plasma renin activity (PRA). PRA is measured specially in case of certain diseases that present with hypertension or hypotension. PRA is also raised in certain tumors.^[21] A PRA measurement may be compared to a plasma aldosterone concentration (PAC) as a PAC/PRA ratio.

Discovery and naming

The name renin = ren + -in, "kidney" + "compound". The most common pronunciation in English is /ˈriːnᵻn/ (long e); /ˈrɛnᵻn/ (short e) is also common, but using /ˈriːnᵻn/ allows one to reserve /ˈrɛnᵻn/ for rennin. Renin was discovered, characterized, and named in 1898 by Robert Tigerstedt, Professor of Physiology, and his student, Per Bergman, at the Karolinska Institute in Stockholm.^[22][23]

See also

• Angiotensin-converting enzyme
• Plasma renin activity
• Renin inhibitor
• Renin stability regulatory element (REN-SRE)

References

External links

• GeneReviews/NCBI/NIH/UW entry on Familial Juvenile Hyperuricemic Nephropathy Type 2
• OMIM entries on Familial Juvenile Hyperuricemic Nephropathy Type 2
• The MEROPS online database for peptidases and their inhibitors: A01.007
• Renin at the US National Library of Medicine Medical Subject Headings (MeSH)

PDB gallery 2bks: CRYSTAL STRUCTURE OF RENIN-PF00074777 COMPLEX  2g24: Ketopiperazine-Based Renin Inhibitors: Optimization of the ""C"" Ring  2ren: STRUCTURE OF RECOMBINANT HUMAN RENIN, A TARGET FOR CARDIOVASCULAR-ACTIVE DRUGS, AT 2.5 ANGSTROMS RESOLUTION  2iko: Crystal Structure of Human Renin Complexed with Inhibitor  2g1y: Ketopiperazine-Based Renin Inhibitors: Optimization of the ""C"" Ring  2g20: Ketopiperazine-Based Renin Inhibitors: Optimization of the C Ring  2g26: Ketopiperazine-Based Renin Inhibitors: Optimization of the ""C"" Ring  2g1n: Ketopiperazine-based renin inhibitors: Optimization of the ""C"" ring  1bil: CRYSTALLOGRAPHIC STUDIES ON THE BINDING MODES OF P2-P3 BUTANEDIAMIDE RENIN INHIBITORS  2iku: Crystal Structure of Human Renin Complexed with Inhibitors  2g1o: Ketopiperazine-Based Renin Inhibitors: Optimization of the ""C"" Ring  2g1r: Ketopiperazine-Based Renin Inhibitors: Optimization of the C Ring  1bim: CRYSTALLOGRAPHIC STUDIES ON THE BINDING MODES OF P2-P3 BUTANEDIAMIDE RENIN INHIBITORS  2fs4: Ketopiperazine-Based Renin Inhibitors: Optimization of the C ring  2il2: Crystal Structure of Human Renin Complexed with Inhibitor  1hrn: HIGH RESOLUTION CRYSTAL STRUCTURES OF RECOMBINANT HUMAN RENIN IN COMPLEX WITH POLYHYDROXYMONOAMIDE INHIBITORS  2bkt: CRYSTAL STRUCTURE OF RENIN-PF00257567 COMPLEX  2g27: Ketopiperazine-Based Renin Inhibitors: Optimization of the ""C"" Ring  1rne: THE CRYSTAL STRUCTURE OF RECOMBINANT GLYCOSYLATED HUMAN RENIN ALONE AND IN COMPLEX WITH A TRANSITION STATE ANALOG INHIBITOR  2g21: Ketopiperazine-Based Renin Inhibitors: Optimization of the ""C"" Ring  1bbs: X-RAY ANALYSES OF PEPTIDE INHIBITOR COMPLEXES DEFINE THE STRUCTURAL BASIS OF SPECIFICITY FOR HUMAN AND MOUSE RENINS  2g1s: Ketopiperazine-Based Renin Inhibitors: Optimization of the C Ring  2i4q: Human renin/PF02342674 complex  2g22: Ketopiperazine-Based Renin Inhibitors: Optimization of the ""C"" Ring