Control of the renal renin system by local factors

CHARLOTTE WAGNER, BOYE L. JENSEN, BERNHARD K. KRAMER, and ARMIN KURTZ

Physiologisches Institut und Medizinische Klinik II der Universitat Regensburg, Regensburg, Germany

Control of the renal renin system by local factors. Local factors,such as prostaglandins (PGs), nitric oxide (NO), and endothelins(ETs), produced in the immediate vicinity of juxtaglomerular (JG)cells can exert significant effects on renin secretion and renin geneexpression. PGE2, as the main renotubular PG, and PGI2, as themain endothelial prostanoid, both stimulate renin secretion andrenin gene expression by activating cAMP formation in JG cells.Although the direct effect of NO on JG cells is less clear, itsoverall effect in vivo seems to be to stimulate the renin system.Evidence is emerging that stimulation by NO is related to thecAMP pathway, and cGMP-induced inhibition of cAMP-phos-phodiesterase III (PDE-III) may mediate this effect. ETs, on theother hand, appear to inhibit the renin system, in particular inthose pathways activated by cAMP, acting via Ca21- and proteinkinase C-related mechanisms. There is increasing evidence thatboth NO and PGs could be involved in the physiological regula-tory mechanisms by which salt intake affects the renin system.

The activity of the renin-angiotensin-aldosterone system,which plays an essential role in salt and blood pressurehomeostasis in the organism, is governed mainly by theplasma activity of the protease renin. Although a variety oftissues can produce renin [1], the major physiologicalimpact has so far been obtained only for renin of renalorigin. Within the kidney, renin is produced by specializedvascular smooth muscle cells (VSMCs) of the afferentarterioles, the so-called granular juxtaglomerular (JG) cells[2, 3]. The last decade has yielded much information on theresponse of renin gene expression and renin secretionunder a variety of physiological and pathophysiologicalconditions, and it is clear that renin gene expression andrenin secretion in renal JG cells are influenced to a similarextent by a number of factors that interact complexly in thecontrol of the renal renin system [4]. Hypotension is wellknown to stimulate renin secretion, and it is generallyagreed that the intraluminal pressure in renal afferentarterioles is an important determinant, not only for reninsecretion but also for renin gene expression: a low perfu-sion pressure stimulates and a high pressure suppresses the

renin system. Further evidence suggests that renal perfu-sion pressure affects the renin system not only by changingpressures in the afferent vessel wall but also by changingthe glomerular filtration rate (GFR). The GFR is a deter-minant of the salt load at the macula densa (MD) of theearly distal tubule, and the MD signaling mechanism is alsolikely to participate in the mechanisms by which theintrarenal perfusion pressure controls the renin system [4].

Klaus Thurau developed intriguing and inspiring ideasabout the functional interplay between the tubular MDcells and the renin-producing JG cells [5]. He proposed atubuloglomerular feedback (TGF) linking the tubular saltload at the early distal tubule to the renal afferent resis-tance via the renin-angiotensin system. This postulate wasconfirmed, almost 30 years later, by Schnermann andBriggs, who demonstrated the absence of TGF in micelacking angiotensin II (Ang II)-AT1a receptors [6], al-though the precise role of renin in this mechanism is still tobe clarified. There is, however, consensus that decreasingsalt transport at the MD increases renin secretion and reningene expression [4]. It is thus conceivable that increasingrenal perfusion pressure might inhibit the renin system alsoby increasing GFR and increasing salt delivery to, andhence transport at, the MD.

Renin gene expression and secretion in vivo also reactsensitively to prolonged changes in salt intake: low saltintake stimulates and high salt intake suppresses the reninsystem [4]. As with the blood pressure, salt intake alsocontrols the renin system by feedback. The most prominentfeedback mechanism controlling the renin system is medi-ated by Ang II, which is generated by the successiveproteolytic activities of renin and Ang I-converting enzyme.Blockade of Ang II-AT1 receptors or diminished Ang IIformation by converting enzyme inhibitors stimulates reninsecretion and renin gene expression powerfully. Con-versely, Ang II itself inhibits renin secretion in vivo and invitro [4].

LOCAL FACTORS CONTROLLING RENIN GENEEXPRESSION AND SECRETION

Apart from the previously mentioned well-documentedmechanisms controlling the renin system, interest is nowfocusing also on the role of local factors for the control of

Key words: prostaglandins, endothelins, juxtaglomerular cells, nitric oxide,cAMP-phosphodiesterase III, renin gene expression, renin-angiotensinsystem, cyclooxygenase, macula densa.

© 1998 by the International Society of Nephrology

Kidney International, Vol. 54, Suppl. 67 (1998), pp. S-78–S-83

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the renin system. A role for local factors was, in principle,already implicit in the influence of the MD on the reninsystem, but interest has been restimulated by the observa-tion that endothelial cells modulate the function of neigh-boring VSMCs via autacoids such as prostaglandins (PGs),nitric oxide (NO), endothelins (ETs), endothelium-derivedhyperpolarizing factor. It is now known that synthesis of the“classic” endothelial autacoids is not restricted to endothe-lial cells but is found also in several renal cell types. Theseautacoids have substantial effects on renin secretion andrenin gene expression, both in vivo and in vitro.

ROLE OF PROSTAGLANDINS IN THE CONTROL OFTHE RENIN SYSTEM

Sites of prostaglandin production in the juxtaglomerulararea

The prerequisite for cell synthesis of PGs and congenersis the presence of cyclooxygenase (COX), which occurs intwo isoforms (COX-I and -II). Although most cell typesexpress COX, certain cells, such as the renal proximaltubule cells, which comprise the bulk of the renal mass, donot [7]. Within the kidney papillary, interstitial cells havethe highest capacity for PG synthesis [7–9]. PGs of papillaryorigin are, however, less likely to be local factors control-ling renin secretion so that sites of PG formation in thevicinity of the renin-producing JG cells must be considered.Afferent arterioles, in fact, are capable of producing PGsand prostacyclin [10]. It is likely that not only endothelialcells but also the VSMCs can produce PGs. Glomeruli andmesangial cells, also close to the JG cells, also synthesizePGs [11]. Finally, the tubular cells of the late thick ascend-ing limb of Henle (TALH) including the MD may berelevant also, as these cells constitutively express relativelyhigh levels of COX-II [8, 12].

Effect of prostaglandins on renin secretion and reningene expression

In vivo experiments show consistently that COX inhibi-tors, if they affect renin secretion, decrease it, whereas PGsgiven into the renal artery stimulate renin secretion. Thissuggests that the overall effect of COX products on reninsecretion in vivo is stimulation rather than inhibition [13,14]. In vitro experiments in isolated perfused kidneys,isolated glomeruli, and cultured JG cells, moreover, alsoindicate that PGE2 and prostacyclin stimulate renin secre-tion and renin gene expression [15–17]. The stimulatoryeffects of PGE2 and prostacyclin in the JG cells appear tobe mediated by stimulation of cAMP formation [17].

Regulation of prostaglandin formation in thejuxtaglomerular region

Prostaglandin formation in renal afferent arterioles andmesangial cells is stimulated by Ca21 mobilization, such as

by Ang II [10, 11]. Because Ca21-mobilizing hormones, inparticular Ang II, inhibit renin secretion and renin geneexpression [4], it is feasible that increased local PG forma-tion, at least partly, counteracts the inhibition of reninsecretion and renin gene expression by vasoconstrictors.More direct evidence for a physiological regulatory role ofPGs has been obtained for the MD mechanism. There itappears that PGs are, at least in part, required for thestimulation of renin secretion and renin gene expression viathe MD mechanism [13, 18, 19], findings consistent with theexpression of COX-II in MD cells [12].

A regulatory role is also conceivable for PGs derivedfrom late TALH cells. COX-II expression in these cells isstrikingly dependent on salt intake, being enhanced by lowsalt intake [9, 12] and suppressed by high salt intake [9].There is in any case evidence that renocortical productionof PGs is inversely related to salt intake [20], suggestingthat tubular PGs could be involved in the stimulation of therenin system by low salt intake. One study has reportedalready that the COX-II—selective inhibitor meloxicamsignificantly attenuates the increase of renin mRNA andrenal renin content in response to a low-salt diet in rats[21].

ROLE OF NITRIC OXIDE IN THE CONTROL OFRENIN GENE EXPRESSION AND SECRETION

Production sites of nitric oxide in the juxtaglomerulararea

Renal JG cells are surrounded by cells with a highcapacity for NO formation. The endothelial cells of theafferent arterioles express the endothelial-type NO syn-thase (e-NOS) [22]. The neighboring tubular cells of theMD are also a source of NO, because they display a strikingselective expression pattern for the neuronal form of theNO synthase (n-NOS) [23, 24].

Effect of nitric oxide on renin secretion and renin geneexpression

In vivo experiments in humans and in various animalsspecies show consistently, with only few exceptions [25, 26],that inhibitors of NO synthases reduce both plasma reninactivity and renal renin mRNA out of order[20, 27–33].This inhibition by NO-synthase blockers is enhanced byprior stimulation of the renin system by various maneuverssuch as renal hypoperfusion [30, 33, 34], low salt intake [27,28], MD inhibition [20], or Ang II antagonists [29]. Theseexperiments suggest that endogenous NO is a rather non-selective stimulator of the renin system. Stimulation of therenin system by NO is further supported by the observationthat the NO donor nitroprusside increases renin secretionin vivo [30].

The interpretation of maneuvers interfering with NO invivo is, however, hampered by concomitant blood pressurechanges and, hence, activation of cardiovascular reflexes.

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Further experiments have been therefore performed inmodels in which the influence of blood pressure or sympa-thetic nerves are absent or at least well controlled, such asin isolated perfused kidneys. Findings from this model areconsistent with the in vivo findings in that NO-synthaseinhibitors acutely lower renin secretion, whereas NO do-nors stimulate renin secretion promptly [35–37]. As in invivo studies, the inhibition of renin secretion by NO-synthase blockers is enhanced if renin secretion is stimu-lated by reducing perfusion pressure [35], by adding ace-tylcholine to the perfusate [37], or by taking kidneys fromanimals pretreated with a low salt diet [36]. Although allthe in vivo experiments and experiments with isolatedperfused kidney suggest a stimulatory effect of NO on therenin system, the situation is less clear when the effect ofNO-synthase inhibitors or NO donors in more reducedpreparations, such as, kidney slices, microdissected JGapparatuses, or isolated JG cells, is considered. In kidneyslices, NO inhibits, whereas NO antagonists stimulate reninsecretion [38, 39]. In microdissected JG apparatuses withthe MD perfused, renin secretion is stimulated when NOformation in the MD is stimulated but is inhibited when aNO donor is applied directly to the JG cells [40]. A similarresponse is found also in isolated JG cells, in which NOdonors promptly inhibit renin secretion [41, 42]. Thisinhibition, however, reverses to stimulation with a delay ofone to two hours [41]. If JG cells are cocultured withendothelial cells, inhibition of NO release decreases reninsecretion [43].

Taken together, these various findings imply that theprompt stimulation by NO in vivo and in isolated perfusedkidneys requires mediation by mechanisms that are eithermissing or compromised in preparations more reducedthan the isolated perfused kidney. A prime candidate forsuch indirect mediation may indeed be the MD mechanism,as suggested by the experiments with the microdissected JGapparatuses. However, NO donors also stimulate reninsecretion in hydronephrotic kidneys devoid of MD struc-tures [37], suggesting that the MD is not essential for thestimulation of renin secretion by NO. Consistent with thisconclusion are our own data showing that NO donors alsostimulate renin secretion in isolated perfused kidneys withblocked MD function (Kurtz et al, unpublished data). Ittherefore seems unlikely that the presence or absence of anintact MD can account for the different effects of NO seenin perfused kidneys and in more reduced preparations.

These discrepancies may be reconciled by consideringthe second messenger pathways by which NO acts on therenin system. Although NO the best established and mostrelevant of which is the stimulation of soluble guanylatecyclase, which leads to increased cGMP synthesis andhence to increased intracellular cGMP levels. Becausenative NO and NO donors also stimulate cGMP formationin isolated JG cells [41], this classic second messenger

pathway for NO presumably exists in native JG cells. Apartfrom direct activation of cation channels (for which there isno evidence in JG cells), the most characteristic intracellu-lar action of cGMP is the activation of cGMP-dependentprotein kinases (GK). Two such kinases (GK-I and -II)have been identified, and interestingly, both are found inJG cells [44]. Within the kidney, GK-II appears to beexpressed rather selectively in JG cells [45]. GK can beactivated specifically also by membrane-permeable cGMP-derivatives, such as 8-bromo-cGMP or 8-pCPT-cGMP,which are also inhibitors of renin secretion in vitro. Thus,activation of GK by NO may explain inhibition of the reninsystem by NO but not the frequently seen stimulation ofrenin gene expression and secretion.

A third possibility for the action of NO via cGMP isinhibition of a specific class of cAMP-phosphodiesterases,PDE-III [46]. In contrast to the previously mentionedmembrane-permeant cGMP analogs, which have a highaffinity for GK but a very low affinity for PDE-III, nativecGMP has a high affinity for PDE-III. This is importantfunctionally because increased cGMP could increasecAMP by inhibiting cAMP degradation and because cAMPis the best established activator of renin secretion and reningene expression [4]. Recently, we have found that pharma-cological inhibition of PDE-III potently enhances reninsecretion in isolated perfused kidneys (Kurtz et al, unpub-lished observations). Indirect evidence also suggests a rolefor PDE-III in mediating the NO effects on renin secretionin vivo [47]. Although further experiments are required toestablish firmly the relevance of PDE-III for the effects ofNO on renin secretion and renin gene expression, it shouldbe remembered that the stimulation of the renin system byNO is related to the cAMP pathway, as demonstrated in theisolated perfused kidney (Kurtz et al, unpublished obser-vations). Because the stability and the expression of PDE-III in JG cells after isolation are unknown, it is unclearwhether changes of the expression level in vitro can accountfor the divergent effects of NO on renin secretion in vitro.Another possible explanation involving PDE-III is that theenhancement of cAMP levels by cGMP will depend on theintrinsic rate of cAMP formation, that is, adenylate cyclaseactivity. It is conceivable that in vitro cAMP formation inJG cells is attenuated because endogenous activators ofcAMP formation, such as PGs, are missing in isolated JGcells. In this case, activation of GK, and consequentlyinhibition of renin secretion, might predominate in theoverall effect of NO on the renin system.

Regulatory role of nitric oxide in the renin system

Given that the overall effect of NO on the renin systemin vivo is stimulation, the question arises as to whetherchanges of JG NO formation could be utilized physiologi-cally to up- or down-regulate renin gene expression andsecretion. NO synthesis in the JG region has not yet beenmeasured directly. However, n-NOS expression in MD cells

Wagner et al: Local control of the renal renin systemS-80

is clearly up-regulated by salt depletion [48–51]. Given thatthe increased expression of n-NOS is associated withincreased NO formation, MD-related changes of NO for-mation could be a link in the as yet unknown pathway(s) bywhich salt deficiency stimulates renin secretion and reningene expression. This assumption is supported by theobservation that NOS inhibition blunts the stimulation ofthe renin system by low salt intake [27, 28]. MD n-NOS is,moreover, down-regulated by contralateral renal arterystenosis [50], a situation that is known to be associated withsuppression of renin secretion and renin m-RNA levels[34].

There is as yet no evidence for altered e-NOS expressionin the JG region. Assumptions about changes of endothe-lial NO formation in the JG region therefore derive fromgeneral knowledge about the regulation of NO formationin endothelial cells. Acetylcholine is a well-known stimula-tor of NO formation in endothelial cells, and in isolatedkidneys, acetylcholine stimulates renin secretion NO de-pendently [35, 37].

ROLE OF ENDOTHELIN IN THE CONTROL OF THERENIN SYSTEM

Sites of endothelin expression in the juxtaglomerulararea

In contrast to PGs and NO, ET formation has not yetbeen localized to the JG region. Medullary collecting ductcells seem to be a major site of renal ET expression.Endothelial cells, VSMCs, mesangial, tubular, and even JGcells themselves may be ET production sites [52, 53]. TheET family comprises three related peptides (ET-1, -2 and-3). The kidney only expresses ET-1 and ET-3 [54].

Effects of endothelins on renin secretion and renin geneexpression

In vitro experiments on kidneys slices, isolated glomeruli,or cultured JG cells show consistently that ETs inhibit reninsecretion and renin gene expression [44, 55–58]. In culturedmouse JG cells, all three ETs inhibit cAMP-stimulatedrenin secretion and renin gene expression equipotentlyalong an intracellular pathway involving Ca21 and proteinkinase C [44, 58]. In isolated perfused rat kidneys, all threeETs affect renin secretion equipotently [59]. In picomolarconcentrations, ETs tend to increase renin secretion, but inthe nanomolar range, ETs consistently inhibit renin secre-tion, as in isolated JG cells. Finally, administration ofpharmacological doses of ETs also inhibits renin secretionin vivo.

In contrast to the clear effects of exogenous ETs on reningene expression and secretion, information on effects of

endogenous ETs on the renin system is scarce. Administra-tion of effective doses of antagonists for both ETa and ETbreceptors in vivo changes neither plasma renin activity norrenin mRNA levels [60]. In rats with unilateral renal arterystenosis, in which the renin system is activated in thestenosed kidney and suppressed in the intact contralateralkidney, ET antagonists also do not influence the changes ofplasma renin activity nor the changes of renin mRNA ineither kidney [60].

Regulatory role of endothelins for renin secretion andrenin gene expression

Renal artery stenosis significantly up-regulates ET1 andET3 mRNA in the kidney [61]. The inhibition of the reninsystem by ET contrasts with the strong stimulation of reninsecretion and renin mRNA in kidneys with stenosed arter-ies. Enhanced formation of ETs possibly counteracts thestimulation of the renin system by renal hypoperfusion.However, as noted earlier here, ET antagonists changeneither renin secretion nor renin mRNA in hypoperfusedkidneys [60].

ACKNOWLEDGMENTS

The secretarial help and assistance provided by H. Trommer and K-H.Gotz is acknowledged gratefully. The authors’ work is supported by theDeutsche Forschungsgemeinschaft.

APPENDIX

Abbreviations used in this article are: Ang II, angiotensin II; COX,cyclooxygenase; e-NOS, endothelial-type NO synthase; ETs, endothelins;GK, cGMP-dependent protein kinases; GRF, glomerular filtration rate;JG, juxtaglomerular; MD, macula densa; n-NOS, neuronal form of theNO synthase; NO, nitric oxide; PDE-III, cGMP-induced inhibition ofcAMP-phosphodiesterase III; PGs, prostaglandins; TALH, thick ascend-ing limb of Henle; TGF, tubuloglomerular feedback; VSMCs, vascularsmooth muscle cells.

Reprint requests to Armin Kurtz, M.D., Physiologisches Institut, UniversitatRegensburg, D-93040 Regensburg, Germany.E-mail: armin.kurtz@vkl.uni-regensburg.de

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Wagner et al: Local control of the renal renin system S-83