Pituitary Adenylate Cyclase–Activating Polypeptide Stimulates Renin Secretion via Activation of PAC1 Receptors
Matthias Hautmann*,
Ulla G. Friis,
Michael Desch*,
Vladimir Todorov*,
Hayo Castrop*,
Florian Segerer*,
Christiane Otto,
Günther Schütz and
Frank Schweda*
* Institute of Physiology, University of Regensburg, Regensburg, Germany; Department of Physiology and Pharmacology, University of Southern Denmark, Odense C, Denmark; and Division of Molecular Biology of the Cell, German Cancer Research Center, Heidelberg, Germany
Address correspondence to: Dr. Frank Schweda, Institute for Physiology, University of Regensburg, 93040 Regensburg, Germany. Phone: +49-941-9432957; Fax: +49-941-9434315; E-mail: frank.schweda{at}klinik.uni-regensburg.de
Received for publication June 19, 2006.
Accepted for publication February 1, 2007.
Besides of its functional role in the nervous system, the neuropeptidepituitary adenylate cyclase–activating polypeptide (PACAP)is involved in the regulation of cardiovascular function. Therefore,PACAP is a potent vasodilator in several vascular beds, includingthe renal vasculature. Because the kidney expresses both PACAPand PACAP-binding sites, it was speculated that PACAP mightregulate cardiovascular function by direct vascular effectsand indirectly by regulating renin release from the kidneys.PACAP (1-27) stimulated renin secretion from isolated perfusedkidneys of rats 4.9-fold with a half-maximum concentration of1.9 nmol/L. In addition, PACAP stimulated renin release andenhanced membrane capacitance of isolated juxtaglomerular cells,indicating a direct stimulation of exocytotic events. The effectof PACAP on renin release was mediated by the specific PACAPreceptors (PAC1), because PACAP (1-27) applied in concentrationsin the physiologic range (10 and 100 pmol/L) did not enhancerenin release from isolated kidneys of PAC1 receptor knockoutmice (PAC1–/–), whereas it stimulated renin release1.38- and 2.5-fold in kidneys from wild-type mice. Moreover,plasma renin concentration was significantly lower in PAC1–/–compared with their wild-type littermates under control conditionsas well as under a low- or high-salt diet and under treatmentwith the angiotensin-converting enzyme inhibitor ramipril, whereasno differences in plasma renin concentration between the genotypeswere detectable after water deprivation. These data show thatPACAP acting on PAC1 receptors potently stimulates renin release,serving as a tonic enhancer of the renin system in vivo.
The pituitary adenylate cyclase–activating polypeptide(PACAP) is a highly conserved neuropeptide that was originallyidentified by its ability to stimulate cAMP formation in pituitarycells (1). PACAP exists in a 27–[PACAP (1-27)] and a 38–[PACAP(1-38)] amino acid form and shows a high homology with vasoactiveintestinal polypeptide (VIP) (2,3). Whereas both PACAP and VIPbind with the same affinity to the PACAP type II receptors VPAC1and VPAC2, PACAP type I (PAC1) receptors show a high selectivityfor PACAP (2,3).
Besides its function in the central nervous system, where PACAPis involved in learning, circadian rhythmicity, and the releaseof pituitary hormones, PACAP plays a role in peripheral tissues,where it contributes to the regulation of catecholamine synthesis,insulin secretion, and the control of pulmonary and cardiovascularfunction (reviewed in references [2,3]). Therefore, PACAP inducesvasodilation in several vessel types and vascular beds suchas coronary, cerebral, and pulmonary arteries; arteries of theskin; hindquarters; and the uteroplacental circulation (4–10).Moreover, PACAP increases renal blood flow in conscious rats(11) and bears protective effects on myeloma injury of proximaltubular cells (12), providing functional links between PACAPand the kidney. A possible role of PACAP in kidney functionhas also been suggested by the detection of PACAP-binding sitesand PACAP receptor gene expression in the kidney (12–17).In addition, PACAP peptides were found in kidney tissue (18,19).
Several vasoactive hormones affect cardiovascular function bydirect effects on vascular smooth muscle cells and by controllingthe release of renin from renal juxtaglomerular (JG) cells.In general, vasoconstrictor hormones inhibit renin release,whereas vasodilator hormones stimulate the exocytosis of renin(20). Because PACAP potently stimulates cAMP formation in variouscell types and because cAMP is the main intracellular stimulatorof renin secretion in JG cells, we speculated that PACAP directlyenhances renin release from the kidney.
Our data for the first time show that PACAP stimulates reninrelease from isolated perfused kidneys of rats and mice andfrom single JG cells. These effects are mediated mainly by PAC1receptors and seem to be of functional importance for the controlof the renin system in vivo.
Animals
Male Sprague-Dawley rats (280 to 330 g body wt) were obtainedfrom Charles River (Sulzfeld, Germany). PAC1-deficient micethat were used in this study were offspring of N5 heterozygousbreeder pairs of the PAC1 knockout strain that was generatedby Otto et al. (21) and backcrossed into a C57BL/6 background.As reported previously, the majority of PAC1-deficient miceon this genetic background die within the first 2 wk of postnatallife (22). In this study approximately 30% of PAC1–/–survived until weaning. Thereafter, the survivors had no decreasedsurvival rate until the end of the experiments at 12 to 18 wkof age. All animal experiments were performed according to theguidelines for the care and use of laboratory animals publishedby the National Institutes of Health and were approved by thelocal government.
Isolated Perfused Kidney
The isolated perfused kidney model for male rats and male PAC1knockout mice was done as described in detail previously (23,24).Briefly, the animals were anesthetized with an intraperitonealinjection of 100 mg/kg 5-ethyl-5-(1-methylbutyl)-2-thiobarbituricacid (rats) or of 12 mg/kg xylazine and 80 mg/kg ketamine-HCl(mice); the abdominal aorta was cannulated; and the right kidneywas excised, placed in a thermostated moistening chamber (37°C),and perfused at constant pressure (100 mmHg). Finally, the renalvein was cannulated, and samples of the venous perfusate weretaken every 3 min for determination of renin activity. The venousperfusate that was not sampled was either discarded (mouse)or drained back into the perfusate reservoir (rat, recirculatingsystem). The basic perfusion medium consisted of a modifiedKrebs-Henseleit solution (24) supplemented with 6 g/100 ml BSAand human red blood cells (10% hematocrit).
For determination of renin activity, the perfusate samples wereincubated for 1.5 h at 37°C with plasma from bilaterallynephrectomized male rats as renin substrate. The generated angiotensinI (AngI; ng/ml per h) was determined by RIA (Byk & DiaSorinDiagnostics, Taufkirchen, Germany), and renin secretion rateswere calculated as the product of renin activity and venousflow rate (ml/min per g kidney wt) (24).
Patch-Clamp Experiments
Patch-clamp experiments on single rat JG cells were done accordingto the method described previously (25,26). In brief, JG cellswere isolated from rat renal cortex by trypsin and collagenasedigestion and subsequent separation with a Percoll gradientand were transferred to coverslips in RPMI-1640 medium. Theexperiments were performed with an internal solution (in mmol/L):135 K-glutamate, 10 NaCl, 10 KCl, 1 MgCl2, 10 HEPES-NaOH, 0.5Mg-ATP, and 0.3 Na2GTP. Osmolality was 303 mOsmol/kg H2O (pH7.07). The external solution was (in mmol/L) 10 HEPES-NaOH,140 NaCl, 2.8 KCl, 1 MgCl2, 2 CaCl2, 11 glucose, and 10 sucrose;osmolality was approximately 300 mOsmol/kg H2O (pH 7.25), withor without PACAP (1-27) 1 pmol/L.
Renin Release from Primary Cultures of Mouse Renin-Producing JG Cells
JG cells of C57BL/6 mice were isolated as described previously(27). After 20 h, the cultures were washed once and 100 µlof prewarmed culture medium that contained the chemicals tobe tested was added. After 4 h of incubation, renin activitywas determined in supernatants and cell lysates by RIA (27).Renin release rates were calculated as fractional release oftotal active renin [i.e., renin activity released/(renin activityreleased + renin activity remaining in the cells)].
Determination of Renin mRNA Expression in CALU-6 Cells
The pulmonary carcinoma cell line CALU-6 was cultured as describedpreviously (28). Cells were incubated with PACAP (1-27) (10pmol/L to 1 µmol/L) or forskolin (5 µmol/L) for20 h. Thereafter, cells were harvested, and isolation of totalRNA, reverse transcriptase–PCR, and subsequent determinationof renin mRNA and -actin mRNA expression using real-time PCRwas performed as described previously (29).
Plasma Renin Concentration
PAC1+/+ and PAC1–/– mice of either gender (12 to18 wk) were subjected to different protocols:
Control: Standarddiet and tap water ad libitum (n = 16 eachgenotype).
Saltdiets: Standard diet balanced in all respects except fora low(0.02% NaCl; Ssniff, Soest, Germany) or a high (4% NaCl,Ssniff)sodium content (PAC1–/– n = 8; PAC1+/+ n= 16 foreach diet) for 7 d.
Enalapril treatment: Inhibition of angiotensin-convertingenzymewith enalapril (10 mg/kg per d) for 5 d via the drinkingwater(PAC1–/– n = 8; PAC1+/+ n = 16).
Water deprivation:Standard diet; drinking water was removedfor 36 h (n = 8 eachgenotype).
At the end of the treatment periods, venous blood samples (75µl) were taken from the tail vein into hematocrit tubesthat contained 1 µl of 125 mM EDTA. After centrifugation,plasma samples were incubated for 1.5 h at 37°C with plasmafrom bilaterally nephrectomized male rats as renin substrate.The generated AngI (ng/ml per h) was determined by RIA. Becauseno significant differences in the plasma renin concentration(PRC) between male and female mice were detected, both genderswere analyzed together.
Determination of PACAP (1-27) in Plasma and Renal Cortex
The concentration of PACAP (1-27) was determined in the plasmaand in renal cortical tissue of male rats and mice. Blood sampleswere taken into tubes that contained EDTA (1 mg/ml blood) fromthe aorta immediately after induction of anesthesia for kidneyexcision for isolated perfusion. The cortex of the contralateralkidney, not used for isolated perfusion, was taken for the determinationof tissue PACAP concentration. Plasma was used for solid-phaseextraction of the peptides according to the instructions ofthe PACAP (1-27) RIA (Peninsula Laboratories, San Carlos, CA).The PACAP (1-27) concentration in the kidney cortex was determinedby the same RIA according to the method described previouslyby Colwell et al. (18).
Systolic BP and Heart Rate Measurements
Systolic BP and heart rate in PAC1 mice were determined by thetail-cuff method (TSE, Bad Homburg, Germany). Mice were conditionedby placing them into the holding devices on five consecutivedays before the first measurement. BP values of the three subsequentdays were averaged.
Statistical Analyses
Values are given as means ± SEM. Differences betweengroups were analyzed by ANOVA and Bonferroni adjustment formultiple comparisons. In the isolated perfused kidney experiments,the last two values that were obtained within an experimentalperiod were averaged and used for statistical analysis. Pairedt test was used to calculate levels of significance within individualkidneys. P < 0.05 was considered statistically significant.
To test for the effects of PACAP on renin release, we firstinfused PACAP (1-27) into isolated perfused kidneys of rats(Figure 1). PACAP stimulated renin secretion rates in a concentration-dependentmanner with a half-maximum concentration of 1.9 nmol/L. Theeffects on renin secretion started at a concentration of 100pmol/L (from 29.0 ± 4.7 to 48.6 ± 6.0 ng AngI/minper ml/g kidney wt; P < 0.05; n = 5) and reached a plateauat a concentration of 100 nmol/L (142.0 ± 24.9 ng AngI/minper ml/g; P < 0.001 versus control; Figure 1). The stimulationof renin release by PACAP was rapid in onset and completelyreversible after stop of PACAP infusion (Figure 2). Both formsof PACAP, PACAP-27 and PACAP-38, enhanced renin secretion butwith different efficacy (Figure 2). Therefore, PACAP (1-27)at 10 nmol/L increased renin secretion rates 6.3-fold from 27.0± 3.6 to 171 ± 15.7 ng AngI/min per ml/g (P <0.01), whereas PACAP (1-38) stimulated release 3.4-fold from37.8 ± 12.4 to 129.1 ± 11.3 ng AngI/min per ml/g(P < 0.01; P < 0.05 versus PACAP (1-27)). In contrastto the marked effects on renin release, PACAP did not changeperfusate flow of isolated kidneys (data not shown).
Figure 1. Effects of 27–amino acid pituitary adenylate cyclase–activating polypeptide [PACAP (1-27)] on renin secretion rates of isolated perfused rat kidneys. Insert shows the average of the last two values at each concentration of PACAP (1-27). *P < 0.05 versus control (0 nmol/L); #P < 0.01 versus control.
Figure 2. Stimulation of renin secretion rates of isolated perfused kidneys of rats by 10 nmol/L PACAP (1-27) (•) and by 10 nmol/L PACAP (1-38) ().
To clarify whether the stimulation of renin release by PACAPwas directly mediated at the level of the renin-producing cells,we first measured the effects of PACAP on membrane capacitance(Cm) of single rat JG cells by patch-clamp in the whole-cellconfiguration as a measure for secretion. As shown in Figure 3A,for a single trace, the application of PACAP (1-27) 1 pmol/Lresulted in a gradual increase of Cm, with an average changeof Cm of 21.2 ± 4.3%, measured 600 s after the startof PACAP (1-27) administration (P < 0.05; n = 4; Figure 3B).Moreover, PACAP (1-27) concentration-dependently stimulatedrenin release from primary cultures of renin-producing cellsof mice (Figure 4A) and enhanced renin synthesis in the renin-producingcell line CALU-6 25-fold (Figure 4B) (28).
Figure 3. (A) Original recording of membrane capacitance (Cm) in a single rat juxtaglomerular (JG) cell. PACAP (1 pmol/L) was added at the time indicated by the arrow. (B) Relative average changes in Cm as a result of PACAP (1 pmol/L; n = 4; ). The change is calculated as the percentage change in Cm measured before and after 10 min of superfusion with PACAP.
. Time controls without the addition of PACAP (control).
Figure 4. (A) Renin release of primary cultures of renin-producing JG cells that were treated with PACAP (1-27) or forskolin for 4 h (n = 5). (B) Renin mRNA expression of CALU-6 cells that were stimulated with PACAP (1-27) or forskolin for 20 h (n = 5). *P < 0.05 versus control; #P < 0.01 versus control.
We next focused on the receptor type that mediates the stimulationof renin release by PACAP. Because PAC1 receptors are consideredspecific PACAP receptors, we investigated the stimulation ofrenin secretion by PACAP (1-27) in isolated perfused kidneysof PAC1–/– and PAC1+/+. As shown in Figure 5, therewas no difference of renin secretion rates under baseline conditions(PAC1+/+ 69.9 ± 14.1; PAC1–/– 50.8 ±8.5 ng AngI/h per min/g kidney weight; NS) and infusion of PACAP(1-27) stimulated renin secretion rates from kidneys of bothPAC1+/+ and PAC1–/– mice. At high concentrationsof PACAP, such as 10 and 100 nmol/L, renin secretion rates werestimulated to a similar extent in both genotypes (PAC1+/+ 360and 390% of control, P < 0.05, respectively; PAC1–/–330 and 420% of control, P < 0.05, respectively; Figure 5).However, in the low concentration range (10 and 100 pmol/L),PACAP did not stimulate renin secretion rates from PAC1–/–kidneys, whereas it significantly enhanced renin release fromkidneys of wild-type mice (10 pmol/L 138%, P < 0.05; 100pmol/L 250%, P < 0.01; Figure 5). Accordingly, the half-maximumconcentration for PACAP (1-27) was significantly shifted from96 pmol/L in wild-type mice to 4.7 nmol/L in PAC1–/–.In contrast to PACAP, the -adrenoreceptor agonist isoproterenolstimulated renin release from kidneys of PAC1+/+ and PAC1–/–mice to similar extents (Figure 5, insert), indicating thatthe lack of PAC1 receptors did not result in a general attenuationof the stimulation of renin release. To test for a possiblein vivo relevance of the observed in vitro results, we firstdetermined the concentration of PACAP (1-27) in the plasma andcortex of mice and rats (Table 1). PACAP (1-27) was detectedin the plasma of both species at a concentration that was shownto stimulate renin release from whole kidneys and single JGcells (Figures 1, 3, and 5), suggesting a physiologic role ofPACAP in the control of renin release in vivo. Indeed, as shownin Figure 6, PRC was significantly lower in PAC1–/–(120.0 ± 8.7 ng AngI/h per ml; n = 16) compared withPAC1+/+ (201.9 ± 16.7 ng AngI/h per ml; n = 16; P <0.01) under control conditions. PAC1–/– had a slightlylower systolic BP (118.6 ± 1.8 mmHg; n = 16) comparedwith PAC1+/+ (124.3 ± 2.1 mmHg; n = 16; P < 0.05),whereas the heart rate was higher in PAC1–/– (514.9± 8.0/s) than in wild-types (464.8 ± 6.6/s; P< 0.001). PRC of PAC1–/– and PAC1+/+ mice wasregulated by the salt intake, because PRC was significantlylower under a high-salt diet compared with salt restrictionin both genotypes (Figure 7). However, as seen under a normalsalt intake (Figure 6), PRC was significantly lower in PAC1–/–compared with wild-type mice under either salt diet. Similarly,blockade of AngII generation by enalapril significantly increasedPRC in both genotypes (Figure 7). Again, PRC was significantlylower in PAC1–/– mice compared with PAC+/+, indicatingthat PACAP and PAC1 receptors are necessary to evoke the fullstimulation of the renin system by these maneuvers. In contrast,water deprivation for 36 h, a known strong stimulator of therenin system, increased PRC to similar levels in PAC1–/–and PAC1+/+ mice, suggesting that PACAP is dispensable in thisprocess.
Figure 5. Renin secretion rates from isolated perfused kidneys of PAC1 receptor knockout mice (PAC1–/–; ) and their wild-type littermates (PAC1+/+; •) in response to PACAP (1-27) infusion. Insert displays effects of isoproterenol on renin secretion rates. *P < 0.05 versus control (0 nmol/L) same genotype; #P < 0.01 versus control (0 nmol/L) same genotype; +P < 0.05 versus PAC1–/– at same PACAP concentration; xP < 0.01 versus PAC1–/– at same PACAP concentration.
Table 1. Concentration of PACAP(1-27) in the plasma of rats (n = 10), PAC1+/+ mice (n = 10), and PAC1–/– mice (n = 5), as well as in renal cortex tissue of rats (n = 5), PAC1+/+ mice (n = 10) and PAC1–/– mice (n = 5)a
Figure 7. PRC of PAC1+/+ and PAC1–/– mice. For 1 wk, mice were kept on a high-salt diet (4% NaCl), mice were kept on a low-salt diet (0.02% NaCl), mice were treated with the angiotensin-converting enzyme inhibitor enalapril (10 mg/kg body wt per d), or the drinking water was removed for 36 h. *P < 0.05 versus low-salt diet.
PACAP originally was implicated in the control of pituitaryfunction as well as in neurotrophic actions and higher cerebralprocesses (2,3). Moreover, PACAP has profound effects in thevascular system and is involved in the regulation of endocrinefunctions; for instance, PACAP stimulates the release of insulinand the synthesis of catecholamines in the adrenal medulla (2,3).These endocrine effects of PACAP have now been extended by PACAP'sability to stimulate the release of renin from the renin-producingJG cells of the kidney. Therefore, in this study, we providestrong evidence that PACAP potently enhances the release ofrenin from isolated perfused kidneys of rats and mice. Becausethe isolated perfused kidney model allows perfusing the kidneysat a constant perfusion pressure and PACAP did not significantlychange renal vascular resistance, it seems unlikely that hemodynamicchanges indirectly mediate the observed stimulation of reninrelease. However, the isolated perfused kidney is still a complexmodel in which renin release can be influenced by several otherindirect factors, such as the endothelium and changes of tubularfunction. Because both PACAP type 1 and PACAP type 2 receptorsare expressed in tubular cells (12), it seemed plausible thatthe stimulation of renin release by PACAP might have been relatedto changes in tubular function. Therefore, we performed experimentsusing isolated renin-producing cells. Indeed, PACAP (1-27) stimulatedrenin release from primary cultures of JG cells and significantlyenhanced Cm of JG cells, reflecting renin secretion becauseexocytotic events result in an integration of vesicles intothe plasma membrane, thereby enlarging the cell surface andCm (25,30). Although these data clearly suggest a direct cellulareffect of PACAP on renin release, these experiments do not excludethat additional indirect factors contribute to the observedstimulation of renin release from the kidney or, moreover, thatPACAP might regulate the renin system not only in the JG cellsbut also in the renal tubular system, for instance the collectingduct, another site of renal renin expression.
In general, PACAP exerts its biologic actions via activationof two types of G protein–coupled receptors. PAC2 receptorsbind PACAP and VIP with the same affinity, whereas PAC1 receptorshave a 1000-fold higher affinity for PACAP, rendering it a specificPACAP receptor (2,3). Our experiments with isolated perfusedkidneys of mice suggested that both PAC1 receptors and PAC2receptors are involved in the stimulation of renin release byPACAP. Therefore, at high concentrations of PACAP, such as 10or 100 nmol/L, renin release was stimulated to similar extentsin kidneys of wild-type mice and of mice that lacked PAC1 receptors,indicating that this receptor type is not indispensably requiredfor the stimulation of renin secretion in the presence of highPACAP concentrations but that the remaining PAC2 receptors,which are also coupled to a stimulation of cAMP generation,stimulate exocytosis. In contrast, at concentrations of PACAPthat occur in mouse plasma (53 pmol/L), the stimulation of reninsecretion was completely dependent on PAC1 receptors, becauseat this concentration of PACAP (1-27), renin release was markedlystimulated in kidneys of wild-type mice but not in kidneys ofPAC1–/– mice. Therefore, these data suggest thatPAC1–/– receptors should be of functional relevancein vivo. In line with this hypothesis, the PRC of consciousPAC1 knockout mice was significantly lower compared with wild-typemice. The straightforward interpretation of these in vivo datais complicated by the fact that the majority of homozygous PAC1–/–die within the first 2 wk of postnatal life from right heartfailure, caused by pulmonary hypertension (22). Although thesurviving PAC1–/– mice did not display a highermortality compared with wild types, it cannot be excluded thatthe observed differences of PRC are mediated by indirect effectsthat are not related to the lack of PAC1 receptors in the kidney.Because renin release is regulated by BP and PACAP is knownto be a vasodilator, it is reasonable to assume that PAC1–/–mice might have arterial hypertension, which in turn would indirectlysuppress the renal renin system. However, PAC1 mice were nothypertensive compared with their wild-type controls, renderingthis possibility unlikely. It is interesting that PAC1–/–mice have an elevated heart rate, a finding that might be secondaryto low BP or other disturbances of the cardiovascular function,but that in either case indicates an activation of the sympatheticnervous system. Because the sympathetic nervous system is amain stimulator of renin secretion (20), the low PRC in PAC1–/–mice further underlines the functional relevance of this receptortype for the control of the renin system in vivo. This conclusionis strengthened by the finding that PRC of PAC1–/–is lower not only compared with wild types at control conditionsbut also under a high-salt diet, a low-salt diet, and a blockadeof AngII generation by angiotensin-converting enzyme inhibition,indicating that PACAP and PAC1 receptors are necessary for afull stimulation of renin release by these in vivo regulatorsof the renin system. It is interesting that water deprivationstimulated PRC to similar values in both genotypes, indicatingeither that PACAP is not involved in this process or that otherfactors compensate for the lack of PAC1 receptors and that thestimulation of PRC is not generally attenuated in PAC1–/–mice.
Taken together, our data clearly demonstrate that PACAP is apotent stimulator of renin release and that this stimulationis mostly mediated by the specific PACAP receptor PAC1. Moreover,the reduced PRC of PAC1 receptor knockout mice suggests a roleof PACAP and the PAC1 receptor as tonic enhancers of renin secretionin vivo.
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Abstract
Introduction
-actin mRNA expression using real-time PCR was performed as described previously (29). 
).
). The change is calculated as the percentage change in Cm measured before and after 10 min of superfusion with PACAP.
. Time controls without the addition of PACAP (control).
