Why renin is secreted

These quantitative differences, however, are less relevant for the fundamental mechanisms considered in this review. In the adult kidney, renin is synthesized by myofibroblast-like cells that are located in the media layer of renal afferent arterioles at the entrance into the glomerular capillary network Figure 1a. Because of their localization and cuboid-like appearance, these cells are commonly termed juxtaglomerular epithelioid cells.

The cuboid form results from huge intracellular vesicles Figure 1b , which are dependent on the production of glycosylated prorenin. Circumstantial evidence suggests that the renin-producing cells might differentiate from pericytes 4 which are probably also precursors of preglomerular vascular cells and glomerular mesangial cells.

In the normal adult kidney renin-producing cells appear just at the junction between these two cell types, suggesting that these cells remain in an intermediate differentiation state between vascular smooth muscle cells on the one side and mesangial cells on the other. Compatible with this idea is the capability of preglomerular vascular smooth muscle cells and extraglomerular mesangial cells to reversibly switch on and off the renin gene expression even in the adult kidney, that leads to an increase or decrease in the number of renin-producing cells see also below.

Although there is evidence that renin gene expression can be regulated to some extent at the posttranscriptional level, 11 the transcription rate of the renin gene is considered as the essential event that determines the production rate of renin.

Within the renin gene multiple regions have meanwhile been identified that mediate either activation or suppression of renin gene transcription. The enzymatically inactive prorenin which results from cleavage of the pre- signal -peptide can be sorted into two different pathways at the level of the Golgi-apparatus Figure 2.

Sorting of prorenin is either directed to a prominent electron dense vesicular network, or to the constitutive secretory pathway which leads to the direct release of prorenin.

The patho physiological relevance of those prorenin effects, however, is yet unclear. Prorenin can be taken up into cells such as in cardiomyocytes where it may be activated to renin. Only glycosylated prorenin can be directed to the vesicular network in juxtaglomerular cells. A prerequisite for this activation appears to be an acidic intravesicular pH and a specific protease, the nature of which still awaits identification.

Cathepsin B has been considered for a long time as the crucial enzyme for the activation of renin, but this assumption has not be confirmed by recent experiments done in cathepsin B-deficient mice. The release of active renin from the vesicular network into the extracellular space probably involves exocytotic events, which, however, seem to be rather rare and which are yet only poorly understood. Among the numerous members of the v- and t-Snare protein families, which play a role in secretion in a variety of endo- and exocrine cells, 24 only synaptobrevin-2 vamp-2 has so far been discussed to be involved in the secretion of renin.

Thus renin secretion appears to be oppositely controlled by cyclic AMP and by calcium signaling pathways for review see ref. Any maneuver that increases cyclic AMP levels in renin-secreting cells either by activating adenylate cyclase or by inhibiting cAMP degradation strongly stimulates renin secretion by mechanisms that likely involve activation of protein kinase A.

Any maneuver that increases the cytosolic calcium concentration in renin-secreting cells either by inducing calcium release from intracellular stores or by enhancing transmembrane calcium influx potently inhibits renin release. A likely explanation for this ying and yang effect of cAMP and calcium on renin release results from the effect of calcium to lower cAMP levels in renin-secreting cells by inhibiting adenylate cyclase activity 30 , 31 and by activating cAMP phosphodiesterase activity.

A third signaling pathway controlling renin secretion relates to cGMP, which is generated by particulate guanylate cyclase such as by the ANP receptor. The intracellular substrates for A- and G-kinases relevant for renin secretion are yet unknown. Secretion of renin from juxtaglomerular cells at the organ level is controlled by a number of factors that become active in the direct vicinity of renin-secreting cells. These factors comprise neurotransmitters released from sympathetic nerve endings, which are found at high density around renin-secreting cells, ANG II, autacoids released from endothelial or macula densa cells, various hormones and the intraluminal blood pressure in afferent arterioles 26 Figure 3.

Several neurotransmitters and neuropeptides, such as norepinephrine, 39 dopamine, 26 , 40 calcitonin gene-related peptide, 41 vasoactive intestinal peptide 42 and pituitary adenylate cyclase-activating peptide 43 have been found to stimulate renin secretion by stimulating the cAMP pathway, whereas neuropeptide Y 44 inhibits renin secretion by inhibiting cAMP formation.

The tubular macula densa cells and the preglomerular endothelial cells produce the same autacoids, namely nitric oxide and prostaglandins, albeit by different mechanisms. Nitric oxide is generated by nitric oxide synthases NOS-1 and NOS-3 in macula densa and in endothelial cells, respectively. Both nitric oxide and prostaglandins such as PGI 2 and PGE 2 act stimulatory on renin secretion in an additive fashion. If and how the release of renin stimulatory autacoids from preglomerular endothelial cells is regulated and thus contribute to the overall regulation of renin secretion is less understood see ahead.

There is one report in this context indicating that the stimulation of renin production and renin secretion after renal artery stenosis is strictly dependent on prostacyclin; 49 this would suggest an important role of the endothelium in this particular setting. Another report suggests the expression of the metabolic succinate receptor on preglomerular endothelial cells, the activation of which may enhance prostanoid formation. The release of renin stimulatory autacoids from the macula densa cells is probably regulated by the tubular concentration of sodium chloride in the macula densa segment of the distal tubule.

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.

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Stimulation of renin secretion by nitric oxide is mediated by phosphodiesterase 3. It appears that renin plays an important role in maintaining blood pressure in the salt- or volume-depleted state and that it is responsible for the initial phases of renovascular hypertension in any model of this disease process. Renin's part in chronic renovascular hypertension depends on whether or not sodium is permitted to accumulate.

If sodium intake is restricted or if sodium excretion is unimpaired such as in two-kidney renovascular hypertension models , renin continues to play a significant role during the chronic phase. Abstract Renin is a hormone secreted by the juxtaglomerular cells of the kidney; it interacts with a plasma protein substrate to produce a decapeptide prohormone angiotensin I.

Publication types Review.