When is renin released by the kidneys

Experiments designed to study the control of renin at the organ and cellular level are commonly done in laboratory animals and in vitro systems. Fortunately, a series of experiments and comparisons have confirmed that the key features of renin are rather similar in men and laboratory animals. Nonetheless, there appear to be quantitative differences in the number of renin-producing cells in the kidney, the rate of intracellular renin processing, and the rate of renin secretion between species, in the way that renin activity is higher in mice when compared to human subjects, presumably because of a higher activity of the renin gene promoter.

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. This study was supported by German research Foundation. Nguyen G. Renin, pro renin and receptor: an update. Clin Sci ; : — Google Scholar. Ingelfinger JR. Angiotensin-converting enzyme 2: implications for blood pressure and kidney disease. Curr Opin Nephrol Hypertens ; 18 : 79 — Physiology of local renin-angiotensin systems. Physiol Rev ; 86 : — Kurtz A.

Renin release: sites, mechanisms, and control. Annu Rev Physiol ; 73 : — Pan L , Gross KW. Transcriptional regulation of renin: an update. Hypertension ; 45 : 3 — 8. Renin-1 is essential for normal renal juxtaglomerular cell granulation and macula densa morphology. J Biol Chem ; : — And over here, this is the efferent arteriole.

And, of course, the other one would be the afferent arteriole. And in fact, I'm going to reverse this arrow just so there's no confusion about direction of blood flow. I don't want you to be confused about where the blood is flowing.

It's going to be going like that, and this is the afferent arteriole. So I've got my blood vessels labeled. And between the two, I also have the distal convoluted tubule, so let's draw that in. And this is the cells surrounding that distal convoluted tubule. There it is. And there's some very special cells also in here, and I'm going to draw in a different color. And they are the macula densa cells. It's actually part of the tubule, but they're very special.

So I'm going to draw them for that reason. So this is the distal convoluted tubule. And in green, I said the macula densa cells. A lot of names I'm throwing at you. And I want you to start feeling comfortable with these names, because they're actually going to be used quite a bit. Macula densa cells. It's not particularly hard once you get used to the language, but I know it can be confusing to see all these funny words thrown up at you. Now, the next thing I want you to think back about and remember is that arterioles don't have just one layer.

I mean we know that arterioles have multiple layers. The inner layer, the tunica intima, is the endothelial cells, we know that. But there's also smooth muscle cells. We know that there's also a layer called the tunica media that's in here with smooth muscle cells, and I'm going to try to draw some smooth muscle cells right there.

So we have a layer of these smooth muscle cells. And if you look closely under a microscope, you'll see that there's also some interesting cells right here. And I'm drawing them in blue just to highlight that they're different, but they are actually very similar to smooth muscle cells. And so in a way, they're specialized smooth muscle cells. So let me label these two new cell types I've drawn for you.

Actually, I'll label them down here. Smooth muscle cells. And they're on the afferent arteriole side. You'll see them a little bit on the efferent arteriole side as well, but mostly on the afferent arteriole side. Smooth muscles cells, and then you have these juxtaglomerular cells. Talk about a funny word, huh, juxtaglomerular cells. So juxtaglomerular cells are there. And if you looked under a microscope, they'd be full of granules. And so sometimes actually they're even called granular cells.

And so let me draw in some granules just to remind you that that's what people see under a microscope, little green granules in this case. And I'll put them into all of them. And you know that these cells are on both sides of the vessel because, of course, we cut it long ways.

So we're just looking at it as if it's disconnected. But you know these two sides are obviously touching if you thought of it in three dimensions. And now I've talked about four cell types. Let's round it out with the last cell type. This is in orange now. This is the mesangial cell, and mesangial cells are really there for structure. They're really there to hold the whole thing together so that the blood vessels and the nephron are in close contact and structurally sound, so think of them as being there for support reasons.

So these are the mesangial cells. And so combined, if you think about all this stuff together-- remember, this is all the white box in the little picture kind of blown up. If you think about all this stuff together, the macula densa cells-- we've got the endothelial cells, the smooth muscle cells, the juxtaglomerular cells, and the mesangial cells. Put together, this whole thing is the juxtaglomerular apparatus. Kind of a funny word, but it's how people refer to all these cells. A reduction in afferent arteriole pressure causes the release of renin from the JG cells, whereas increased pressure inhibits renin release.

Beta 1 -adrenoceptors located on the JG cells respond to sympathetic nerve stimulation by releasing renin. Specialized cells macula densa of distal tubules lie adjacent to the JG cells of the afferent arteriole.

The macula densa senses the concentration of sodium and chloride ions in the tubular fluid. When NaCl is elevated in the tubular fluid, renin release is inhibited. In contrast, a reduction in tubular NaCl stimulates renin release by the JG cells. When afferent arteriole pressure is reduced, glomerular filtration decreases, and this reduces NaCl in the distal tubule.

This serves as an important mechanism contributing to the release of renin when there is afferent arteriole hypotension, which can be caused by systemic hypotension or narrowing stenosis of the renal artery that supplies blood flow to the kidney.