Hemodynamics and Vascular Regulation

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
JASN April 2007, 18 (4) 1150-1156; DOI: https://doi.org/10.1681/ASN.2006060633

Abstract

Besides of its functional role in the nervous system, the neuropeptide pituitary adenylate cyclase–activating polypeptide (PACAP) is involved in the regulation of cardiovascular function. Therefore, PACAP is a potent vasodilator in several vascular beds, including the renal vasculature. Because the kidney expresses both PACAP and PACAP-binding sites, it was speculated that PACAP might regulate cardiovascular function by direct vascular effects and indirectly by regulating renin release from the kidneys. PACAP (1-27) stimulated renin secretion from isolated perfused kidneys of rats 4.9-fold with a half-maximum concentration of 1.9 nmol/L. In addition, PACAP stimulated renin release and enhanced membrane capacitance of isolated juxtaglomerular cells, indicating a direct stimulation of exocytotic events. The effect of PACAP on renin release was mediated by the specific PACAP receptors (PAC1), because PACAP (1-27) applied in concentrations in the physiologic range (10 and 100 pmol/L) did not enhance renin release from isolated kidneys of PAC1 receptor knockout mice (PAC1−/−), whereas it stimulated renin release 1.38- 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 conditions as well as under a low- or high-salt diet and under treatment with the angiotensin-converting enzyme inhibitor ramipril, whereas no differences in plasma renin concentration between the genotypes were detectable after water deprivation. These data show that PACAP 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 originally identified by its ability to stimulate cAMP formation in pituitary cells (1). PACAP exists in a 27–[PACAP (1-27)] and a 38–[PACAP (1-38)] amino acid form and shows a high homology with vasoactive intestinal polypeptide (VIP) (2,3). Whereas both PACAP and VIP bind with the same affinity to the PACAP type II receptors VPAC1 and VPAC2, PACAP type I (PAC1) receptors show a high selectivity for PACAP (2,3).

Besides its function in the central nervous system, where PACAP is involved in learning, circadian rhythmicity, and the release of 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 cardiovascular function (reviewed in references [2,3]). Therefore, PACAP induces vasodilation in several vessel types and vascular beds such as coronary, cerebral, and pulmonary arteries; arteries of the skin; 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 proximal tubular cells (12), providing functional links between PACAP and the kidney. A possible role of PACAP in kidney function has also been suggested by the detection of PACAP-binding sites and 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 by direct effects on vascular smooth muscle cells and by controlling the 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 various cell types and because cAMP is the main intracellular stimulator of renin secretion in JG cells, we speculated that PACAP directly enhances renin release from the kidney.

Our data for the first time show that PACAP stimulates renin release from isolated perfused kidneys of rats and mice and from single JG cells. These effects are mediated mainly by PAC1 receptors and seem to be of functional importance for the control of the renin system in vivo.

Materials and Methods

Animals

Male Sprague-Dawley rats (280 to 330 g body wt) were obtained from Charles River (Sulzfeld, Germany). PAC1-deficient mice that were used in this study were offspring of N5 heterozygous breeder pairs of the PAC1 knockout strain that was generated by Otto et al. (21) and backcrossed into a C57BL/6 background. As reported previously, the majority of PAC1-deficient mice on this genetic background die within the first 2 wk of postnatal life (22). In this study approximately 30% of PAC1−/− survived until weaning. Thereafter, the survivors had no decreased survival rate until the end of the experiments at 12 to 18 wk of age. All animal experiments were performed according to the guidelines for the care and use of laboratory animals published by the National Institutes of Health and were approved by the local government.

Isolated Perfused Kidney

The isolated perfused kidney model for male rats and male PAC1 knockout mice was done as described in detail previously (23,24). Briefly, the animals were anesthetized with an intraperitoneal injection of 100 mg/kg 5-ethyl-5-(1-methylbutyl)-2-thiobarbituric acid (rats) or of 12 mg/kg xylazine and 80 mg/kg ketamine-HCl (mice); the abdominal aorta was cannulated; and the right kidney was excised, placed in a thermostated moistening chamber (37°C), and perfused at constant pressure (100 mmHg). Finally, the renal vein was cannulated, and samples of the venous perfusate were taken every 3 min for determination of renin activity. The venous perfusate that was not sampled was either discarded (mouse) or drained back into the perfusate reservoir (rat, recirculating system). The basic perfusion medium consisted of a modified Krebs-Henseleit solution (24) supplemented with 6 g/100 ml BSA and human red blood cells (10% hematocrit).

For determination of renin activity, the perfusate samples were incubated for 1.5 h at 37°C with plasma from bilaterally nephrectomized male rats as renin substrate. The generated angiotensin I (AngI; ng/ml per h) was determined by RIA (Byk & DiaSorin Diagnostics, Taufkirchen, Germany), and renin secretion rates were calculated as the product of renin activity and venous flow rate (ml/min per g kidney wt) (24).

Patch-Clamp Experiments

Patch-clamp experiments on single rat JG cells were done according to the method described previously (25,26). In brief, JG cells were isolated from rat renal cortex by trypsin and collagenase digestion and subsequent separation with a Percoll gradient and were transferred to coverslips in RPMI-1640 medium. The experiments were performed with an internal solution (in mmol/L): 135 K-glutamate, 10 NaCl, 10 KCl, 1 MgCl2, 10 HEPES-NaOH, 0.5 Mg-ATP, and 0.3 Na2GTP. Osmolality was 303 mOsmol/kg H2O (pH 7.07). 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), with or 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 μl of prewarmed culture medium that contained the chemicals to be tested was added. After 4 h of incubation, renin activity was determined in supernatants and cell lysates by RIA (27). Renin release rates were calculated as fractional release of total active renin [i.e., renin activity released/(renin activity released + 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 described previously (28). Cells were incubated with PACAP (1-27) (10 pmol/L to 1 μmol/L) or forskolin (5 μmol/L) for 20 h. Thereafter, cells were harvested, and isolation of total RNA, reverse transcriptase–PCR, and subsequent determination of renin mRNA and β-actin mRNA expression using real-time PCR was performed as described previously (29).

Plasma Renin Concentration

PAC1+/+ and PAC1−/− mice of either gender (12 to 18 wk) were subjected to different protocols:

  1. Control: Standard diet and tap water ad libitum (n = 16 each genotype).

  2. Salt diets: Standard diet balanced in all respects except for a low (0.02% NaCl; Ssniff, Soest, Germany) or a high (4% NaCl, Ssniff) sodium content (PAC1−/− n = 8; PAC1+/+ n = 16 for each diet) for 7 d.

  3. Enalapril treatment: Inhibition of angiotensin-converting enzyme with enalapril (10 mg/kg per d) for 5 d via the drinking water (PAC1−/− n = 8; PAC1+/+ n = 16).

  4. Water deprivation: Standard diet; drinking water was removed for 36 h (n = 8 each genotype).

At the end of the treatment periods, venous blood samples (75 μl) were taken from the tail vein into hematocrit tubes that contained 1 μl of 125 mM EDTA. After centrifugation, plasma samples were incubated for 1.5 h at 37°C with plasma from bilaterally nephrectomized male rats as renin substrate. The generated AngI (ng/ml per h) was determined by RIA. Because no significant differences in the plasma renin concentration (PRC) between male and female mice were detected, both genders were analyzed together.

Determination of PACAP (1-27) in Plasma and Renal Cortex

The concentration of PACAP (1-27) was determined in the plasma and in renal cortical tissue of male rats and mice. Blood samples were taken into tubes that contained EDTA (1 mg/ml blood) from the aorta immediately after induction of anesthesia for kidney excision for isolated perfusion. The cortex of the contralateral kidney, not used for isolated perfusion, was taken for the determination of tissue PACAP concentration. Plasma was used for solid-phase extraction of the peptides according to the instructions of the PACAP (1-27) RIA (Peninsula Laboratories, San Carlos, CA). The PACAP (1-27) concentration in the kidney cortex was determined by the same RIA according to the method described previously by Colwell et al. (18).

Systolic BP and Heart Rate Measurements

Systolic BP and heart rate in PAC1 mice were determined by the tail-cuff method (TSE, Bad Homburg, Germany). Mice were conditioned by placing them into the holding devices on five consecutive days before the first measurement. BP values of the three subsequent days were averaged.

Statistical Analyses

Values are given as means ± SEM. Differences between groups were analyzed by ANOVA and Bonferroni adjustment for multiple comparisons. In the isolated perfused kidney experiments, the last two values that were obtained within an experimental period were averaged and used for statistical analysis. Paired t test was used to calculate levels of significance within individual kidneys. P < 0.05 was considered statistically significant.

Results

To test for the effects of PACAP on renin release, we first infused PACAP (1-27) into isolated perfused kidneys of rats (Figure 1). PACAP stimulated renin secretion rates in a concentration-dependent manner with a half-maximum concentration of 1.9 nmol/L. The effects on renin secretion started at a concentration of 100 pmol/L (from 29.0 ± 4.7 to 48.6 ± 6.0 ng AngI/min per ml/g kidney wt; P < 0.05; n = 5) and reached a plateau at a concentration of 100 nmol/L (142.0 ± 24.9 ng AngI/min per ml/g; P < 0.001 versus control; Figure 1). The stimulation of renin release by PACAP was rapid in onset and completely reversible after stop of PACAP infusion (Figure 2). Both forms of PACAP, PACAP-27 and PACAP-38, enhanced renin secretion but with 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 from 37.8 ± 12.4 to 129.1 ± 11.3 ng AngI/min per ml/g (P < 0.01; P < 0.05 versus PACAP (1-27)). In contrast to the marked effects on renin release, PACAP did not change perfusate flow of isolated kidneys (data not shown).

Figure 1.
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.
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 PACAP was 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-cell configuration as a measure for secretion. As shown in Figure 3A, for a single trace, the application of PACAP (1-27) 1 pmol/L resulted in a gradual increase of Cm, with an average change of Cm of 21.2 ± 4.3%, measured 600 s after the start of PACAP (1-27) administration (P < 0.05; n = 4; Figure 3B). Moreover, PACAP (1-27) concentration-dependently stimulated renin release from primary cultures of renin-producing cells of mice (Figure 4A) and enhanced renin synthesis in the renin-producing cell line CALU-6 25-fold (Figure 4B) (28).

Figure 3.
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.
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 stimulation of renin release by PACAP. Because PAC1 receptors are considered specific PACAP receptors, we investigated the stimulation of renin secretion by PACAP (1-27) in isolated perfused kidneys of PAC1−/− and PAC1+/+. As shown in Figure 5, there was 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 both PAC1+/+ and PAC1−/− mice. At high concentrations of PACAP, such as 10 and 100 nmol/L, renin secretion rates were stimulated to a similar extent in both genotypes (PAC1+/+ 360 and 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 from kidneys of wild-type mice (10 pmol/L 138%, P < 0.05; 100 pmol/L 250%, P < 0.01; Figure 5). Accordingly, the half-maximum concentration for PACAP (1-27) was significantly shifted from 96 pmol/L in wild-type mice to 4.7 nmol/L in PAC1−/−. In contrast to PACAP, the β-adrenoreceptor agonist isoproterenol stimulated renin release from kidneys of PAC1+/+ and PAC1−/− mice to similar extents (Figure 5, insert), indicating that the lack of PAC1 receptors did not result in a general attenuation of the stimulation of renin release. To test for a possible in vivo relevance of the observed in vitro results, we first determined the concentration of PACAP (1-27) in the plasma and cortex of mice and rats (Table 1). PACAP (1-27) was detected in the plasma of both species at a concentration that was shown to stimulate renin release from whole kidneys and single JG cells (Figures 1, 3, and 5), suggesting a physiologic role of PACAP in the control of renin release in vivo. Indeed, as shown in Figure 6, PRC was significantly lower in PAC1−/− (120.0 ± 8.7 ng AngI/h per ml; n = 16) compared with PAC1+/+ (201.9 ± 16.7 ng AngI/h per ml; n = 16; P < 0.01) under control conditions. PAC1−/− had a slightly lower systolic BP (118.6 ± 1.8 mmHg; n = 16) compared with 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 was regulated by the salt intake, because PRC was significantly lower under a high-salt diet compared with salt restriction in both genotypes (Figure 7). However, as seen under a normal salt 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 increased PRC in both genotypes (Figure 7). Again, PRC was significantly lower in PAC1−/− mice compared with PAC+/+, indicating that PACAP and PAC1 receptors are necessary to evoke the full stimulation of the renin system by these maneuvers. In contrast, water deprivation for 36 h, a known strong stimulator of the renin system, increased PRC to similar levels in PAC1−/− and PAC1+/+ mice, suggesting that PACAP is dispensable in this process.

Figure 5.
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.

Figure 6.
Figure 6.

Plasma renin concentration (PRC; top), systolic BP (middle), and heart rate (bottom) in PAC1−/− and PAC1+/+ mice.

Figure 7.
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.

View this table:
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

Discussion

PACAP originally was implicated in the control of pituitary function as well as in neurotrophic actions and higher cerebral processes (2,3). Moreover, PACAP has profound effects in the vascular system and is involved in the regulation of endocrine functions; for instance, PACAP stimulates the release of insulin and the synthesis of catecholamines in the adrenal medulla (2,3). These endocrine effects of PACAP have now been extended by PACAP's ability to stimulate the release of renin from the renin-producing JG cells of the kidney. Therefore, in this study, we provide strong evidence that PACAP potently enhances the release of renin from isolated perfused kidneys of rats and mice. Because the isolated perfused kidney model allows perfusing the kidneys at a constant perfusion pressure and PACAP did not significantly change renal vascular resistance, it seems unlikely that hemodynamic changes indirectly mediate the observed stimulation of renin release. However, the isolated perfused kidney is still a complex model in which renin release can be influenced by several other indirect factors, such as the endothelium and changes of tubular function. Because both PACAP type 1 and PACAP type 2 receptors are expressed in tubular cells (12), it seemed plausible that the stimulation of renin release by PACAP might have been related to changes in tubular function. Therefore, we performed experiments using isolated renin-producing cells. Indeed, PACAP (1-27) stimulated renin release from primary cultures of JG cells and significantly enhanced Cm of JG cells, reflecting renin secretion because exocytotic events result in an integration of vesicles into the plasma membrane, thereby enlarging the cell surface and Cm (25,30). Although these data clearly suggest a direct cellular effect of PACAP on renin release, these experiments do not exclude that additional indirect factors contribute to the observed stimulation of renin release from the kidney or, moreover, that PACAP might regulate the renin system not only in the JG cells but also in the renal tubular system, for instance the collecting duct, another site of renal renin expression.

In general, PACAP exerts its biologic actions via activation of two types of G protein–coupled receptors. PAC2 receptors bind PACAP and VIP with the same affinity, whereas PAC1 receptors have a 1000-fold higher affinity for PACAP, rendering it a specific PACAP receptor (2,3). Our experiments with isolated perfused kidneys of mice suggested that both PAC1 receptors and PAC2 receptors are involved in the stimulation of renin release by PACAP. Therefore, at high concentrations of PACAP, such as 10 or 100 nmol/L, renin release was stimulated to similar extents in kidneys of wild-type mice and of mice that lacked PAC1 receptors, indicating that this receptor type is not indispensably required for the stimulation of renin secretion in the presence of high PACAP concentrations but that the remaining PAC2 receptors, which are also coupled to a stimulation of cAMP generation, stimulate exocytosis. In contrast, at concentrations of PACAP that occur in mouse plasma (53 pmol/L), the stimulation of renin secretion was completely dependent on PAC1 receptors, because at this concentration of PACAP (1-27), renin release was markedly stimulated in kidneys of wild-type mice but not in kidneys of PAC1−/− mice. Therefore, these data suggest that PAC1−/− receptors should be of functional relevance in vivo. In line with this hypothesis, the PRC of conscious PAC1 knockout mice was significantly lower compared with wild-type mice. The straightforward interpretation of these in vivo data is complicated by the fact that the majority of homozygous PAC1−/− die within the first 2 wk of postnatal life from right heart failure, caused by pulmonary hypertension (22). Although the surviving PAC1−/− mice did not display a higher mortality compared with wild types, it cannot be excluded that the observed differences of PRC are mediated by indirect effects that are not related to the lack of PAC1 receptors in the kidney. Because renin release is regulated by BP and PACAP is known to be a vasodilator, it is reasonable to assume that PAC1−/− mice might have arterial hypertension, which in turn would indirectly suppress the renal renin system. However, PAC1 mice were not hypertensive compared with their wild-type controls, rendering this possibility unlikely. It is interesting that PAC1−/− mice have an elevated heart rate, a finding that might be secondary to low BP or other disturbances of the cardiovascular function, but that in either case indicates an activation of the sympathetic nervous system. Because the sympathetic nervous system is a main stimulator of renin secretion (20), the low PRC in PAC1−/− mice further underlines the functional relevance of this receptor type for the control of the renin system in vivo. This conclusion is strengthened by the finding that PRC of PAC1−/− is lower not only compared with wild types at control conditions but also under a high-salt diet, a low-salt diet, and a blockade of AngII generation by angiotensin-converting enzyme inhibition, indicating that PACAP and PAC1 receptors are necessary for a full stimulation of renin release by these in vivo regulators of the renin system. It is interesting that water deprivation stimulated PRC to similar values in both genotypes, indicating either that PACAP is not involved in this process or that other factors compensate for the lack of PAC1 receptors and that the stimulation of PRC is not generally attenuated in PAC1−/− mice.

Conclusion

Taken together, our data clearly demonstrate that PACAP is a potent stimulator of renin release and that this stimulation is mostly mediated by the specific PACAP receptor PAC1. Moreover, the reduced PRC of PAC1 receptor knockout mice suggests a role of PACAP and the PAC1 receptor as tonic enhancers of renin secretion in vivo.

Disclosures

None.

Acknowledgments

This study was financially supported by the Deutsche Forschungsgemeinschaft (to F.S.).

Footnotes

  • Published online ahead of print. Publication date available online at www.jasn.org.

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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, Frank Schweda
JASN Apr 2007, 18 (4) 1150-1156; DOI: 10.1681/ASN.2006060633
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