RENNIN Property

storage temp. 

−20°C

form 

powder

color 

slightly brown

Merck 

13,8218

Safety

Hazard Codes 

Xn

Risk Statements 

36/37/38-42

Safety Statements 

22-24-26-36/37

WGK Germany 

1

F 

3-10

Hazard and Precautionary Statements (GHS)

RENNIN Chemical Properties,Usage,Production

Properties

Mr. 38 kDa. Renin has high specificity on AGT and cleaves Ang I from AGT. The cleavage specificity is determined by the [HPF]-domain on Ang I. Renin recognizes this signature domain and cleaves the peptide bond at two aa residues after the domain. The [HPF]-domain is highly conserved among vertebrates (see Angiotensin II), indicating that similar functional constraints could be present in other vertebrate renins. Renin can be activated by proteolysis, acidic pH, and low temperature.

Gene, mRNA, and mRNA

REN1 is located at chromosome 1q32.1 in humans. Renin is synthesized as an inactive form called prorenin but recent studies indicated that prorenin can bind to the renin receptor and activate the cleavage site reversibly by changing the conformation of the prosegment. REN1 is synthesized mainly by the kidney but mRNA is also found in many other tissues, including the heart, brain, and adrenal glands.

Synthesis and release

The macula densa, in response to the change in the Na concentration in the distal tubules, signals the juxtaglomerular cells to release renin. Renin is stored in granules and the secretion is stimulated by the β-adrenergic response and cAMP augmentation. The release of active renin from the kidney is inhibited by increased arterial pressure or Ang II, and an increased intracellular Ca concentration. This is in contrast to the other secretory cells, in which an increase in intracellular calcium usually enhances the depletion of secretory granules. Thus, this is often called the calcium paradox. The regulatory elements of the promoter of the renin gene were termed the “renin enhancer.” This was later found to be a compound regulatory element with several stimulatory and inhibitory activities. In the renin enhancer, cAMP response elements have been identified. Besides transcriptional regulation, a posttranslational regulation at the untranslated region (a 200 bp segment beyond the coding region) was also known, where the mRNA stability can be enhanced by cAMP stimulation.

Receptors

The renin receptor (ATP6AP2) binds to both prorenin and renin. The renin receptor gene is located on chromosome Xp11. in humans. The major known function is that the binding increases the catalytic activity of renin on AGT by 5–10 fold: the Km for AGT (in the absence of the renin receptor) is 1μM and the Km of the membrane-bound renin receptor complex is 0.15μM. The renin receptor is abundantly expressed in the heart, brain, and placenta, and lower expressions are found in the kidney and liver. In the brain, the renin receptor is expressed in the subfornical organ, paraventricular nucleus, supraoptic nucleus, tractus solitaries nucleus, and rostral ventrolateral medulla, which are likely involved in the regulation of cardiovascular and volume regulation. Global knockout of the renin receptor is embryonically lethal. Genome data also suggest that the orthologous renin receptor is present in other vertebrates, including teleosts and tetrapods.

Antagonist

Aliskiren is the first in a new class of orally active, nonpeptide, low-molecular-weight renin inhibitors. It is a transition-state mimetic with favorable physicochemical properties, including high aqueous solubility (350mg/mL at pH 7.4) and high hydrophilicity (log Poct/water=2.45 at pH 7.4), which are important properties for oral bioavailability. Aliskiren is designed through a combination of molecular modeling techniques and crystal structure elucidation, and it effectively reduces the blood pressure as a monotherapy as well in combination therapy.

Biological functions

Renin is the rate-limiting enzyme that initiates the cascade generating the angiotensin peptides that regulate blood pressure, cell growth, apoptosis, and electrolyte balance. Renin is a hormone that ultimately integrates cardiovascular and renal function in the control of blood pressure as well as salt and volume homeostasis. Prorenin is activated by proteolytic enzymes such as trypsin and kallikrein. Acid treatment (optimal pH at 3.3) and low temperature fully or partially (~15%) activate prorenin. The binding of prorenin to the renin receptor changes the conformation of the prosegment to expose the active site to activate the enzyme.

Description

Renin is the rate-limiting enzyme for the initiation of the cascade of the renin-angiotensin system. Plasma renin activity is a marker for hypertension. This is a drug target for hypertension and renal disease. In the late 18th century, renin was discovered based on the observation that the injection of saline extracts from fresh rabbit kidneys into other rabbits increased arterial blood pressure.

Uses

Rennin is a milk coagulant that is an enzyme obtained from the abo- masum portion of the stomach of suckling mammals. it is most active at ph 3.8. one part purified rennin will coagulate more than five million parts of milk. the commercial extract of rennin is termed rennet. it is used to coagulate milk in making cheese, junket, and custard. see rennet.

Definition

An enzyme secreted by cellslining the stomach in mammals thatis responsible for clotting milk. Itacts on a soluble milk protein (caseinogen),which it converts to theinsoluble form casein. This ensuresthat milk remains in the stomachlong enough to be acted on by protein-digesting enzymes.

Biological Functions

Renin is an enzyme that is synthesized and stored in the renal juxtaglomerular apparatus and that catalyzes the formation of a decapeptide, angiotensin I, from a plasma protein substrate. Renin has a narrow substrate specificity that is limited to a single peptide bond in angiotensinogen, a precursor of angiotensin I. Renin is considered to control the rate-limiting step in the ultimate production of angiotensin II. Control of renin secretion by the juxtaglomerular apparatus is important in determining the plasma renin concentration.
Three generally accepted mechanisms are involved in the regulation of renin secretion. The first depends on renal afferent arterioles that act as stretch receptors or baroreceptors. Increased intravascular pressure and increased volume in the afferent arteriole inhibits the release of renin. The second mechanism is the result of changes in the amount of filtered sodium that reaches the macula densa of the distal tubule. Plasma renin activity correlates inversely with dietary sodium intake. The third renin secretory control mechanism is neurogenic and involves the dense sympathetic innervation of the juxtaglomerular cells in the afferent arteriole; renin release is increased following activation of 1-adrenoceptors by the neurotransmitter norepinephrine.
Angiotensin II, the primary end product of the renin–angiotensin system, acts on the juxtaglomerular cells to inhibit the release of renin; this process is therefore a negative feedback mechanism. The half-life of renin in the circulation is 10 to 30 minutes, with inactivation occurring primarily in the liver. Small amounts of renin are eliminated by the kidneys. Pure human renin has been used to develop specific inhibitors of the enzyme. Low-molecular-weight orally effective renin inhibitors are under development.

Clinical Use

Renin inhibitors can be used for the treatment of hypertension. In current medical practice, PRA is the indicator of RAS overactivity and is more commonly treated using either ACE blockers and/or AT1 blockers rather than a direct oral renin inhibitor. ACE inhibitors and/or AT1 blockers are also part of the standard treatment after a heart attack. The diagnosis of kidney cancer includes a juxtaglomerular cell tumor (reninoma), Wilms’ tumor, and renal cell carcinoma, all of which may produce renin and lead to hypertension in patients.

Structure and conformation

Renin is a highly specific endopeptidase whose only known function is to generate angiotensin I (Ang I) from angiotensinogen (AGT), initiating a cascade of reactions that produces elevated blood pressure and increased sodium retention by the kidney. REN1 is a protein coding gene with 406 aa residues in humans; it forms an aspartyl protease.