right, angII regulates renin release. The regulation is through angII receptor on JG, which can be blocked by losartan. it is the same receptor on aldosterone secreting cells.

Renin belongs to a family of enzymes referred to as aspartic proteases, which also includes the enzymes pepsin, cathepsin, and chymosin.[13] Renin is a monospecific enzyme that displays remarkable specificity for its only known substrate, angiotensinogen.

Classically, our understanding of the function and importance of renin relates entirely to its role in the generation of A II. The reaction catalyzed by renin is the rate-limiting step in A II formation. Neither A I nor A II can be synthesized at all in the absence of renin (or, as discussed below, nonproteolytically activated pro-renin). In addition, the conversion of angiotensinogen to A I is favored by a 5,000-fold concentration gradient, making it unlikely that substrate availability could limit A II production.[10]

Renin is produced through activation of its enzymatically inactive precursor, pro-renin. Pro-renin is synthesized as a preprohormone, in that it contains a signal peptide that leads the inactive molecule to the exterior of the cell.[16] Pro-renin concentration in human plasma is approximately 10-fold greater than the concentration of renin,[17] and the proportion of circulating pro-renin is increased in patients with diabetes.[18,19] The enzymatic inactivity of pro-renin is attributable to a 43-amino-acid N-terminal pro-peptide that covers the active site and blocks access to angiotensinogen.

Pro-renin may be rendered enzymatically active in 2 ways, proteolytic and nonproteolytic activation. Proteolytic activation occurs via the actual removal of the pro-peptide chain. Most proteolytic activation of pro-renin occurs in the juxtaglomerular cells of the kidney leading to the production of active renin.[20] Nonproteolytic activation is a 2-step process that allows pro-renin to acquire enzymatic activity without removal of the pro-segment. This process involves unfolding of the pro-peptide chain away from the enzymatic cleft followed by an additional conformational change.[21] Nonproteolytic activation can be induced in vitro by exposure to cold and/or low pH[22,23] and, as discussed below, through binding to the (pro)renin receptor.

The active peptide in the renin-angiotensin system (RAS) is angiotensin II (Ang II), which exerts its effects by binding to a receptor on the cell surface. There are four known types of Ang II receptor, which were first classified based on their sensitivity to certain pharmacological agents – sartans and PD123319. The type 1 receptor is the target of anti-hypertensive drugs known as ARBs (angiotensin receptor blockers).

Blood Pressure Regulation

Blood pressure is regulated by the renin-angiotensin system (RAS). The liver, and often fat tissue, produces the protein angiotensinogen. This is cut by the enzyme renin into angiotensin I (Ang I). Angiotensin I is then cut by angiotensin converting enzyme (ACE) into angiotensin II (Ang II). Angiotensin II is the active protein, or peptide, in the system. It binds to its specific receptor on the surface of cells in the adrenal gland, kidney, liver, heart, brain, and blood vessels. There are several types of Ang II receptors, but the one important in blood pressure regulation is the angiotensin II type 1 receptor (AT1R).

The Angiotensin II Type 1 Receptor (AT1)

The AT1 receptor is selectively inhibited by sartans. In mammals, the receptor is 359 amino acids in length and was initially characterized from human liver. The receptor has a molecular mass of 41 KDa, though it is 65 KDa when glycosylated. Humans have one AT1; rodents have two – AT1a and AT1b. This makes some interpretations from studies in rodent models to humans difficult, though both receptor types are more than 90% homologous to the human AT1 and AT1a has been shown to be the subtype to which the human subtype is most identical.

The AT1 receptor plays an important role in Ang II signaling, which will be discussed in a later article. It is a seven transmembrane G-protein coupled receptor. When Ang II binds, it results in a conformational change that activates a signal cascade, by acting as a scaffold for signaling proteins, resulting in the regulation of tyrosine kinase activity. The AT1 receptor mediates most of the known physiological actions of Ang II, including the regulation of arterial blood pressure, water balance, hormone secretion, and renal function. However, there is a relatively low abundance of the receptor in Ang II target tissues, but it is found to some extent in the heart, kidney, liver, brain, endometrium, vascular smooth muscle cells, lung macrophages, and adrenals.
Angiotensin II Type 2 Receptor (AT2)

The AT2 receptor is inhibited by PD123319 and related compounds; it shares only 32-34% homology with AT1, though they both bind Ang II. The AT2 receptor is expressed widely in fetal tissues, and it is restricted after birth to the brain, adrenals, heart, kidney, myometrium, and ovary; but predominantly in mesenchymal tissues in the tongue, skin, and diaphragm. The number of these receptors is increased in the case of vascular injury, myocardial infarction, congestive heart failure, renal failure, brain ischemia, and nerve transsection.

Some research has suggested that the AT2 receptor keeps the AT1 receptor’s actions in balance by resulting in the opposite effects upon Ang II binding. Activation of AT2 results in vasodilation and natriuresis. Unlike AT1, AT2 receptors signal through Gi protein coupling and phosphatase activation. However, this counteraction has not been seen in the central responses in the brain.

Titre du document / Document title
The renin receptor: the facts, the promise and the hope
Auteur(s) / Author(s)
NGUYEN Genevieve ; BURCKLE Celine ; SRAER Jean-Daniel ;
Résumé / Abstract
Purpose of review The renin-angiotensin system plays a major role in the control of blood pressure and of salt balance, but it is also involved in physiological and pathological processes, development, inflammation and cardiac hypertrophy. A concept has emerged suggesting that these effects are due to a local activation of the renin-angiotensin system. The search for a receptor of renin was based on the idea that tissue (pro)renin is taken up from the circulation and on data suggesting that renin per se has cellular effects independent of angiotensin II. Recent findings Endothelial cells and cardiac myocytes bind (pro)renin via the mannose-6-phosphate receptor, mainly a clearance receptor as no cellular effect has been specifically attributed to prorenin binding. A functional receptor was cloned recently. It mediates intracellular signalling by activating the mitogen activated protein kinases, extracellular signal regulated kinases 1 and 2, and acts as a co-factor by increasing the efficiency of angiotensinogen cleavage by receptor-bound (pro)renin. The receptor is abundantly expressed in heart, brain, placenta and eye, compared with a lower expression in liver and kidney. In normal human kidney and heart, it is localized in the mesangium and in the coronary and kidney artery, associated with smooth-muscle cells and co-localized with renin. Summary This receptor provides a functional role for prorenin and may help to understand the physiological and pathological role of elevated levels of prorenin and of local activation of the renin-angiotensin system. From a practical point of view, it questions the need for a pharmacological compound blocking (pro)renin binding and activity as an alternative to the classical inhibitors of the renin-angiotensin system.
Revue / Journal Title
Current opinion in nephrology and hypertension ISSN 1062-4821
Source / Source
2003, vol. 12, no1, pp. 51-55 [5 page(s) (article)]

Blockers of the renin–angiotensin system (RAS) are widely used for the treatment of cardiovascular and renal diseases. It is generally assumed that the beneficial effects of these drugs are due, at least in part, to blockade of the generation or action of angiotensin (Ang) II at tissue sites [1]. According to this concept, Ang II is generated at tissue sites rather than in circulating blood. Multiple lines of evidence support this idea [2–5]. Remarkably, however, although several RAS components are locally expressed [e.g. ACE, Ang II type 1 (AT1) and type 2 (AT2) receptors] [6–8], thereby allowing such local activity, renin is not [9,10]. Thus, the renin required for local Ang production is sequestered from the circulation, i.e. is kidney-derived. Importantly, renin has an inactive precursor, prorenin. Prorenin is released constitutively from the kidney, and its blood plasma levels are 10-fold higher than those of renin [11].

it is now believed that the M6P/IGF2R serves as a clearance receptor for renin/prorenin [31].

This leaves the recently cloned (pro)renin receptor as the most promising candidate for tissue uptake of circulating renin/prorenin. This receptor, a 350-amino acid protein with a single transmembrane domain, was first identified on cultured human mesangial cells [24]. The receptor binds prorenin with higher affinity than renin [32] and, unlike the M6P/IGF2R, does not internalize these proteins. Since binding to the receptor allowed prorenin to become catalytically active without proteolytic cleavage of the prosegment, the activation must have been due to a conformational change. Interestingly in this regard, an 8.9 kDa fragment of the (pro)renin receptor called M8-9 is known to co-precipitate with a vacuolar proton-ATPase (V-ATPase) [33]. V-ATPases play important roles in acidification of intracellular compartments and cellular pH homeostasis, thereby providing a potential link between the (pro)renin receptor and acid activation. Since there is only one gene for the (pro)renin receptor and the M8-9 protein, it is likely that both proteins derive from the same transcript. The M8-9 fragment corresponds to the cytoplasmic domain, the transmembrane domain and part of the extracellular domain of the receptor.

occurred in AT1A receptor-deficient mice [43]. Since such mice no longer display the normal (constrictor) response to Ang II [44], the effect of the (pro)renin receptor antagonist in these mice cannot be explained solely on the basis of suppression of local Ang generation. Interestingly, phospho-p42/p44 MAPK as well as phospho-p38 MAPK and phospho-Jnk MAPK were up-regulated in the diabetic kidney, both in WT mice and in AT1A receptor-deficient mice, and (pro)renin receptor blockade (but not ACE inhibition) fully normalized this increased phosphorylation [43]. Finally, Schefe et al. [45] identified the transcription factor promyelocytic zinc finger (PLZF) protein as a direct protein interaction partner of the C-terminal domain of the (pro)renin receptor by yeast 2-hybrid screening and coimmunoprecipitation. Importantly, on activation of the receptor by renin, PLZF is translocated to the nucleus and represses transcription of the (pro)renin receptor itself, thus creating a short negative feedback loop. In other words: high renin levels, as occurring during RAS blockade, will suppress (pro)renin receptor expression, thereby preventing excessive receptor activation. Whether prorenin exerts the same effect is currently unknown.

Overexpression of the human (pro)renin receptor in rats resulted in elevated blood pressure, increased plasma aldosterone and/or increased cyclooxygenase-2 expression in the renal cortex [46,47]. Since such overexpression was not accompanied by changes in plasma renin activity or tissue Ang II content, Ang-independent effects of the receptor may underlie this phenotype.

threewalkers wrote:
renin negative feedback receptor

the receptor regulate renin is angII receptor, which is the same receptor as aldosterone, which is reguated by AngII. Only in this way, can we explain the changes after ACE inhibitor and losartan usage.

dude, renin is an enzyme. it has no receptor. where are you getting this from? it just converts angiotensinogen into Ag-I.

right, angII regulates renin release. The regulation is through angII receptor on JG, which can be blocked by losartan. it is the same receptor on aldosterone secreting cells.