Vascular endothelium, particularly in the lungs, has an enzyme, angiotensin converting enzyme ACE , that cleaves off two amino acids to form the octapeptide, angiotensin II AII , although many other tissues in the body heart, brain, vascular also can form AII.
The renin-angiotensin-aldosterone pathway is not only regulated by the mechanisms that stimulate renin release, but it is also modulated by natriuretic peptides released by the heart. These natriuretic peptides acts as an important counter-regulatory system. Therapeutic manipulation of this pathway is very important in treating hypertension and heart failure.
ACE inhibitors , AII receptor blockers and aldosterone receptor blockers , for example, are used to decrease arterial pressure, ventricular afterload, blood volume and hence ventricular preload, as well as inhibit and reverse cardiac and vascular hypertrophy.
Cardiovascular Physiology Concepts Richard E. Klabunde, PhD. Klabunde, all rights reserved Web Design by Jimp Studio. The release of prostaglandin E 2 from the macula densa and the adjacent thick ascending limb of Henle's loop increases when the concentration of sodium chloride in the tubular fluid falls. Macula densa derived nitric oxide appears to exert a more tonic permissive effect on renin secretion.
A reduction of glomerular filtration occurs when the renal perfusion pressure falls below the autoregulatory range of glomerular filtration rate. The renal perfusion pressure indeed is a very powerful minute to minute regulator of renin secretion. Renin secretion from the kidneys is inversely related to the renal perfusion pressure. It appears as if a threshold pressure exists, below which renin secretion increases with falling blood pressure 55 , 56 Figure 4.
It appears as if the baroreceptor mechanism by itself probably does not directly trigger the secretion process of renin but rather modulates cAMP triggered renin secretion. As a consequence the slope of the pressure-secretion curve is variable depending on the basal secretory activity. The curve becomes steeper during inhibition of the RAAS 59 or during states of salt depletion 59 , 60 and flattened by inhibition of nitric oxide formation. The hypothesis that Cx40 hemichannels allow mechanosensitive calcium influx into renin-producing cells is a tempting but merely speculative hypothesis at the moment.
The before mentioned findings on the mechanisms controlling renin secretion were mostly obtained in isolated preparations or in laboratory animals under specific conditions that do not provide direct information about the relative contribution of the different pathways to the integrative control of renin secretion in vivo.
The secretion of renin in the normal healthy organism is in the low range, meaning that there is no major regulatory range left to further suppress renin synthesis and renin secretion beyond the normal situation. The stimulatory effect of the SNS on renin secretion is mediated by two mechanisms. In vivo plasma renin activity correlates inversely with arterial blood pressure. It has been shown for dogs that the intrarenal baroreceptor control of renin secretion is important for the day to day setting of the blood pressure.
Supportive evidence for the relevance of the intrarenal baroreceptor of renin secretion for systemic blood pressure regulation was recently provided by the observation that mice with defective baroreceptor function due to impaired function of Cx40 show massive hyper-reninemia and hypertension. Normal plasma renin concentrations in parallel with hypertension indicate a defective baroreceptor function, which contributes to the development or maintenance of hypertension.
Since the kidneys produce and excrete substantial amounts of prostanoids the question about the role of prostaglandins for the control of renin secretion is obvious. Mice with a disruption of the gene for COX-2 have low plasma renin activities but display also structural malformations of the kidney.
COX activity inhibiting drugs, including preferential COX-2 blockers hardly exert an effect on plasma renin in normal beings, suggesting that the contribution of prostaglandins to basal renin secretion is a minor one. In patients with salt wasting diseases such as Bartters disease, COX inhibitors markedly lower plasma renin activity, which is elevated in these patients.
Conversely, there appears to be a requirement of nitric oxide for the enhancement of renin secretion in response to low sodium intake. A possible mediator function of prostaglandins is also conceivable for the stimulation of renin secretion by renal artery stenosis. It has been found that the vascular expression of COX-2 79 and the production of prostaglandin E2 80 are increased in stenotic kidneys in parallel with increased renin secretion.
As a consequence, drugs used to inhibit the formation of ANG II, such as direct renin inhibitors, angiotensin-converting enzyme inhibitors and ANG II AT1-receptor blockers all lead to increases in circulating renin, reflecting enhanced secretion from the kidneys. As mentioned before the secretion of renin is influenced by calcium in a striking unsual manner, namely in a way that an increase in the cytosolic calcium concentration inhibits the release of renin. The influence of extracellular calcium on parathyroid hormone secretion is mediated by a calcium sensor protein, which can be pharmacologically activated by so called calcium mimetics.
First evidence suggests that calcium mimetics in fact also lower plasma renin activity in human subjects and in rats. The mechanisms controlling renin secretion as considered so far have predominantly addressed rapid changes of secretion occurring in the time frame of minutes, which are due to acute changes of the release of stored renin.
If changes of intrarenal perfusion pressure or of salt balance last over days or longer, regardless whether they activate or inhibit renin secretion, then the number of renin-secreting cells changes in parallel Figure 5.
Before considering this particular process, it should be recalled that the appearance of renin-producing cells in the developing kidney follows a characteristic spatiotemporal pattern. Once a particular vessel segment has matured, renin expression is switched off, but the capability to reactivate renin expression is preserved. In the mature kidney renin-expressing cells are therefore confined to the most distal portion of the preglomerular vascular tree.
Cells of the preglomerular vessels still have the capability to retransform into renin-producing cells. They do so in a typical retrograde direction starting from the vascular pole back to arcuate or interlobar arteries. It appears as if this phenotype switch is an all or nothing phenomenon, meaning that recruited renin-producing cells display a very similar ultrastructure to that of typical juxtaglomerular epithelioid cells.
It is probably more than the activation of the renin gene as indicated by the observation that also the expression patterns of smooth muscle filaments 7 and of connexins change 93 with the phenotype. Well-known situations that lead to retrograde recruitment of renin-producing cells along the vessel wall are situations in which the renal perfusion pressure falls. It appears not unlikely therefore that the renal baroreceptor mechanisms not only regulate acute renin secretion but also the long-term transformation of vascular smooth muscle cells into renin producers.
Well-known situations that lead to a hypertrophy of the juxtaglomerular apparatus are salt losing diseases 91 , 95 or the abuse of diuretics. It is not unlikely that the enhanced formation of intrarenal prostaglandin E 2 in these situations is a major trigger for the switch on of renin expression in extraglomerular mesangial cells.
Pharmacological inhibition 98 , 99 or genetic interruption of the RAAS , also leads to compensatory increases in the number of renin-producing cells and in consequence of renin secretion, and this thwarts to some extent the intended blockade the RAAS. It appears as if the magnitude of compensatory increase in renin secretion depends on the degree of RAAS inhibition. It is probably not a direct effect of ANG II that influences the phenotypic switch underlying the appearance or disappearance of renin-producing cells but rather the functional consequences of ANG II action such as changes in blood pressure and salt balance.
Even years after its discovery renin still is a demanding molecule. The main physiological regulators of renal renin synthesis and secretion, such as the SNS, prostaglandins, blood pressure, and extracellular volume have been identified, but their mode of action at the level of renin-producing cells is still less understood.
It is well established that the number of renin-producing cells in the kidney is variable, depending on demand, but the understanding of the molecular events that lead to a reversible transformation of renal vascular smooth muscle cells into renin-producing cells is still at its beginning.
Open questions exist also about the physiological meaning of circulating prorenin, which reaches higher levels in the circulation than renin itself, at least in human subjects. Progress made by the generation of suitable genetically engineered mice as well as promising sophisticated gene profiling analyses of renin-producing cells raise hope that open fundamental questions will receive an answer in the near future.
The author thanks Hayo Castrop for critical reading and for helpful discussions. This study was supported by German research Foundation. Nguyen G. Renin, pro renin and receptor: an update. Clin Sci ; : — Google Scholar.
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It helps to maintain blood pressure and fluid balance in the body. Alternative names for angiotensin The different forms of angiotensin are denoted by Roman numerals, angiotensin I—IV. What is angiotensin? Angiotensin II has effects on: Blood vessels — it increases blood pressure by causing constriction narrowing of the blood vessels Nerves: it increases the sensation of thirst, the desire for salt, encourages the release of other hormones that are involved in fluid retention.
How is angiotensin controlled? What happens if I have too much angiotensin? What happens if I have too little angiotensin? Last reviewed: Oct Prev.
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