Store-operated calcium influx inhibits renin secretion

Frank Schweda1, Günter A. J. Riegger2, Armin Kurtz1, and Bernhard K. Krämer2

1 Institut für Physiologie I and 2 Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, D-93040 Regensburg, Germany


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

On the basis of evidence that changes in the extracellular concentration of calcium effectively modulate renin secretion from renal juxtaglomerular cells, our study aimed to determine the effect of calcium influx activated by depletion of intracellular calcium stores on renin secretion. For this purpose we characterized the effects of the endoplasmatic Ca2+-ATPase inhibitors thapsigargin (300 nM) and cyclopiazonic acid (20 µM) on renin secretion from isolated perfused rat kidneys. We found that Ca2+-ATPase inhibition caused a potent inhibition of basal renin secretion as well as renin secretion activated by isoproterenol, bumetanide, and by a fall in the renal perfusion pressure. The inhibitory effect of Ca2+-ATPase inhibition on renin secretion was reversed within seconds by lowering of the extracellular calcium concentration into the submicromolar range but was not affected by lanthanum, gadolinium, flufenamic acid, or amlodipine. These data suggest that calcium influx triggered by release of calcium from internal stores is a powerful mechanism to inhibit renin secretion from juxtaglomerular cells. The store-triggered calcium influx pathway in juxtaglomerular cells is apparently not sensitive to classic blockers of the capacitative calcium entry pathway.

thapsigargin; cyclopiazonic acid; endoplasmatic calcium-adenosinetriphosphatase; isolated perfused rat kidney


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

IT HAS BEEN PROPOSED FOR DECADES that calcium plays an unusual role in the control of renin secretion from renal juxtaglomerular cells in the way that an increase in the calcium concentration inhibits the exocytosis of renin, whereas in other secretory cells calcium supports secretion. The assumption of inhibitory effects on renin secretion is based on the evidence that lowering of the extracellular concentration of calcium stimulates renin secretion (1, 4, 9, 14, 24, 27, 29, 39) and that calcium-mobilizing hormones inhibit renin secretion (9, 18, 27), dependent on the availability of extracellular calcium (4, 24, 27, 29, 39). Whether it is the internal calcium release or the transmembrane calcium influx that is relevant for the control of renin secretion cannot be distinguished from previous experiments because external calcium is required for both filling of internal stores and for influx into the cytosol. Moreover, also the routes along which calcium could enter juxtaglomerular cells, in particular the role of voltage-gated calcium channels, are subject to controversy (3, 7, 8, 12, 15, 17, 19, 23, 30). Although we could not find electrophysiological evidence for a functional role of voltage-gated calcium channels in renal juxtaglomerular cells (19), we found that angiotensin II, which is a classic inhibitor of renin secretion, mobilized calcium from internal stores and transiently increased the calcium permeability of juxtaglomerular cells (17). The nature of this angiotensin II-triggered calcium influx pathway and its relevance for renin secretion, however, is yet unknown.

During the last decade evidence has been elaborated that release of calcium from internal stores can trigger transmembrane calcium influx through a signal related to the filling state of internal calcium stores (2, 26). The resulting calcium-release-activated calcium current (Icrac) flowing across the plasma membrane is detectable by using the patch-clamp technique (11). Such a store-operated calcium influx is seen in a broad variety of cells (25), but its existence in renal juxtaglomerular cells has not been demonstrated till now. We therefore wondered whether such a calcium store-regulated calcium influx also exists in renal juxtaglomerular cells and what its impact for renin secretion may be.

Store-triggered calcium influx can experimentally be activated by inhibition of calcium uptake into internal stores through the inhibition of endoplasmatic Ca2+-ATPases (33, 34). We therefore characterized the effects of the Ca2+-ATPase inhibitors thapsigargin and cyclopiazonic acid on renin secretion from isolated perfused rat kidneys. Our results indicate that store-triggered calcium influx acts as a powerful inhibitor mechanism for renin secretion.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Isolated perfused rat kidney. Male Sprague-Dawley rats (280-330 g body wt), having free access to commercial pellet chow and tap water, were obtained from the local animal house and used throughout. Kidney perfusion was performed in a recycling system (30). In brief, the animals were anesthetized with 100 mg/kg of 5-ethyl-5-(1-methylbutyl)-2-thiobarbituric acid (Trapanal, Byk Gulden, Konstanz, Germany). Volume loss during the preparation was substituted by intermittent injections of physiological saline via a catheter inserted into the jugular vein. After opening of the abdominal cavity by a midline incision, the right kidney was exposed and placed in a thermoregulated metal chamber. The right ureter was cannulated with a small polypropylene tube (PP-10) that was connected to a larger polyethylene catheter (PE-50). After intravenous heparin injection (2 U/g) the aorta was clamped distal to the right renal artery so that the perfusion of the right kidney was not disturbed during the following insertion of the perfusion cannula in the aorta distal to the clamp. After ligation of the large vessels branching off the abdominal aorta, a double-barreled perfusion cannula was inserted into the abdominal aorta and placed close to the aortic clamp distal to the origin of the right renal artery. After ligation of the aorta proximal to the right renal artery, the aortic clamp was quickly removed and perfusion was started in situ with an initial flow rate of 8 ml/min. By using this technique, a significant ischemic period of the right kidney was avoided. The right kidney was excised, and perfusion at constant pressure (100 mmHg) was established. To this end the renal artery pressure was monitored through the inner part of the perfusion cannula (Statham Transducer P 10 EZ), and the pressure signal was used for feedback control of a peristaltic pump. The perfusion circuit was closed by draining the venous effluent via a metal cannula back into a reservoir (200-220 ml). The basic perfusion medium, which was taken from a thermostated (37°C) reservoir, consisted of a modified Krebs-Henseleit solution containing (in mM) all physiological amino acids in concentrations between 0.2 and 2.0 mM, 8.7 glucose, 0.3 pyruvate, 2.0 L-lactate, 1.0 alpha -ketoglutarate, 1.0 L-malate, and 6.0 urea. The perfusate was supplemented with 6 g/100 ml bovine serum albumin, 1 mU/100 ml vasopressin 8-lysine, and freshly washed human red blood cells (10% hematocrit). Ampicillin (3 mg/100 ml) and flucloxacillin (3 mg/100 ml) were added to inhibit possible bacterial growth in the medium. To improve the functional preservation of the preparation, the perfusate was continuously dialyzed against a 25-fold volume of the same composition but lacking erythrocytes and albumin. For oxygenation of the perfusion medium the dialysate was gassed with a 94% O2-6% CO2 mixture. Under these conditions both glomerular filtration and filtration fraction remain stable for at least 90 min at values of ~1 ml · min-1 · g-1 and 7%, respectively (30). Perfusate flow rates were obtained from the revolutions of the peristaltic pump, which was calibrated before and after each experiment. Renal flow rate and perfusion pressure were continuously monitored by a potentiometric recorder. After the reperfusion loop perfusate flow was established, rates usually stabilized within 15 min. Stock solutions of the drugs to be tested were dissolved in freshly prepared perfusate and infused into the arterial limb of the perfusion circuit directly before the kidneys at 3% of the rate of perfusate flow.

For determination of perfusate renin activity aliquots (~0.1 ml) were drawn in intervals of 5 min from the arterial limb of the circulation and the renal venous effluent, respectively. The samples were centrifuged at 1,500 g for 15 min, and the supernatants were stored at -20°C until assayed for renin activity. 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 (ng · ml-1 · h-1) was determined by radioimmunoassay (Sorin, Biomedica, Düsseldorf). Renin secretion rates were calculated as the product of the arteriovenous differences of renin activity and the perfusate flow rate (ml/min).

Five kidneys were used for each experimental protocol. Kidney weights were 1.45 ± 0.18 g for the right kidney and 1.35 ± 0.16 g for the left kidney. As there were no significant differences in the results when the data were related to the left or the right kidney weight, all data in RESULTS are related on the weight of the right kidney.

Chemicals. Isoproterenol, thapsigargin, cyclopiazonic acid, gadolinium (III)-chloride, lanthanum chloride, and flufenamic acid were purchased from Sigma Chemical (Deisenhofen, Germany).

For lowering calcium concentration into the submicromolar range, we either added the calcium chelator EGTA (3.12 mM; Sigma Chemical) to the perfusate or we used a nominally calcium-free dialysate.

Statistics. For evaluation of significance of a certain experimental maneuver on renin secretion, all renin secretion rates obtained within this experimental period (4 values) were averaged and compared with the average values of renin secretion of an adjoining experimental period. Student's paired t-test was used to calculate levels of significance within individual kidneys. P < 0.05 was considered significant.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Effects of Ca2+-ATPase inhibition on renin secretion and perfusate flow. Basal flow rates and renin secretion rates from the isolated rat kidneys reached stable plateaus 10-15 min after onset of artificial perfusion (Fig. 1). To deplete internal calcium stores we used the Ca2+-ATPase inhibitor thapsigargin (300 nM). Thapsigargin produced a marked fall in renin secretion (P < 0.01) (Fig. 1, bottom), whereas perfusate flow rates at constant pressure declined only moderately (not significant) (Fig. 1, top). Addition of isoproterenol (10 nM) to the perfusate in the presence of thapsigargin increased flow rates (not significant) (Fig. 1, top) and restored basal renin secretion rates (Fig. 1, bottom). If isoproterenol was administered in the absence of thapsigargin, renin secretion increased eightfold over basal (P < 0.01) (Fig. 1, bottom). Flow changes were not statistically significant. Apparently, thapsigargin not only inhibited basal renin secretion but also markedly attenuated the stimulability by beta -adrenoreceptor activation.


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Fig. 1.   Effects of thapsigargin (300 nM) and isoproterenol (isoprot; 10 nM) on renin secretion rate and perfusate flow (). open circle , Time control without thapsigargin. Values are means ± SE.

A similar attenuation of isoproterenol-stimulated renin secretion was achieved with cyclopiazonic acid (20 µ M), another established endoplasmatic Ca2+-ATPase inhibitor, which inhibited renin secretion also after a significant prestimulation with isoproterenol, suggesting that inhibition of Ca2+-ATPase does not only prevent stimulation of renin secretion but also reverses a stimulated renin secretion (Fig. 2, bottom). Again, perfusate flow was not altered significantly by inhibition of the endoplasmatic Ca2+-ATPase (Fig. 2, top).


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Fig. 2.   Effects of isoproterenol (10 nM) and cyclopiazonic acid (20 µM) on perfusate flow and renin secretion rate. Values are means ± SE. For statistics, see text.

Similarly, stimulation of renin secretion two- to threefold by inhibiting the macula densa salt transport with bumetanide (100 µM) (P < 0.05 vs. control) or lowering the perfusion pressure to 40 mmHg (P < 0.05 vs. control) was reversed by adding thapsigargin (Fig. 3) (P < 0.05 vs. stimulated values for bumetanide and lowered pressure), indicating that the inhibitory action of Ca2+-ATPase blockers is not restricted to a specific pathway of stimulation of renin secretion. Perfusate flow did not change significantly after either administration of bumetanide or addition of thapsigargin. As expected, reduction of perfusion pressure to 40 mmHg led to a significant decrease in perfusate flow.


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Fig. 3.   Effects of bumetanide (100 µM; ) or reduction of perfusion pressure to 40 mmHg (open circle ) and thapsigargin (300 nM) on perfusate flow and renin secretion rate. Values are means ± SE. For statistics, see text.

Relevance of extracellular calcium for the inhibitory effects of Ca2+-ATPase inhibitors. The next set of experiments was designed to evaluate the relevance of extracellular calcium for the effects of Ca2+-ATPase inhibitors on renin secretion. For this purpose renin secretion was prestimulated by isoproterenol, which then was significantly attenuated by thapsigargin (P < 0.05) (Fig. 4). In the presence of isoproterenol plus thapsigargin, the concentration of extracellular calcium was then rapidly lowered from 3 mM into the lower submicromolar range by the addition of 3.12 mM EGTA to the perfusate. This maneuver almost instantaneously reversed the inhibition of renin secretion by thapsigargin (Fig. 4) and tended to increase perfusate flow (not significant). The effect of EGTA was completely reversible, because, after withdrawal of EGTA, renin secretion values rapidly fell to below control (Fig. 4).


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Fig. 4.   Effects of lowering extracellular calcium by addition of EGTA on the effects of thapsigargin. Stimulation of renin secretion with isoproterenol (10 nM) and concomitant administration of thapsigargin (300 nM). Extracellular calcium concentration was lowered into the submicromolar range by adding EGTA (3.12 mM) to the perfusate over a period of 10 min, following recovery period by stopping EGTA infusion. Values are means ± SE. * P < 0.05.

To confirm the calcium dependency of the inhibitory effects of thapsigargin on renin secretion, we performed a similar set of experiments as described above but used a different way of lowering the calcium concentration in the perfusate. By switching from the standard dialysate containing 3 mM calcium to a nominally calcium-free dialysate the calcium concentration in the perfusate was lowered into the submicromolar range. This procedure led to a significant increase in perfusate flow and a moderate increase in renin secretion (Fig. 5). Addition of isoproterenol led to a significant stimulation of renin secretion at low calcium () as well as at normal extracellular calcium concentrations (open circle ). As seen in previous studies this increase was more pronounced at low extracellular calcium concentrations compared with the normal calcium concentration. Administration of thapsigargin in this situation suppressed renin secretion rate significantly at normal calcium but failed to attenuate renin secretion under low-calcium conditions (Fig. 5).


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Fig. 5.   Effects of calcium-free perfusate on renin secretion and flow rate and on the effects of isoproterenol (10 nM) and thapsigargin (300 nM; ). open circle , Time control with physiological extracellular calcium concentrations and isoproterenol and thapsigargin perfusion. Values are means ± SE. For statistics, see text.

Effects of blockers of store-operated calcium channels and L-type calcium channels on thapsigargin-induced inhibition of renin secretion. Assuming that the inhibitory effect of Ca2+-ATPase blockade on renin secretion was causally related to calcium influx from the extracellular space, we tested the effects of drugs that were previously reported to block store- operated calcium entry, such as lanthanum, gadolinium, or flufenamic acid (13, 32). As shown in Fig. 6, however, neither lanthanum nor flufenamic acid or gadolinium was capable of reversing the inhibitory effect of thapsigargin on renin secretion. Moreover, they exerted no significant effect on perfusate flow. Also blocking L-type calcium channels by amlodipine (5 µM) had no effect on the renin suppressing effects of thapsigargin (Fig. 6). In contrast, lowering extracellular calcium into the submicromolar range by adding EGTA (3.12 mM) led to an increase in renin secretion to isoproterenol-stimulated values, indicating a reversal of the thapsigargin effect (Fig. 6).


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Fig. 6.   Renin secretion rates as percent of values after isoproterenol stimulation. Values are means ± SE. Effect of lanthanum (lant; 50 µM), flufenamic acid (flufen; 100 µM), gadolinium (gado; 50 µM), amlodipine (amlo; 5 µM), and EGTA (3.12 mM) on renin secretion rate and on thapsigargin (thap; 300 nM) effect on renin secretion. Iso, isoproterenol (10 nM). n.s., Not significant. # P < 0.001 vs. isoproterenol alone.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The purpose of our study was to examine the effect of calcium influx triggered by depletion of internal stores on renin secretion from renal juxtaglomerular cells. To empty internal calcium stores we used a widely accepted maneuver, namely, inhibition of calcium uptake into internal stores via the inhibition of endoplasmatic Ca2+-ATPases by using thapsigargin and cyclopiazonic acid. Both drugs have been shown to increase intracellular calcium concentration primarily by inhibition of endoplasmatic Ca2+-ATPase and thereby blocking the calcium transport from the cytosol into the intracellular calcium stores. The resulting calcium depletion of the stores activates a calcium influx from the extracellular space via store-operated calcium channels (6, 33, 34, 36, 37). The activation of store-operated calcium channels seems restricted to stores sensitive to inositol triphosphate (10), a known second messenger of angiotensin II.

Our data now show that inhibitors of Ca2+-ATPase in fact are highly effective on renin secretion, in the way that they strongly inhibit basal and stimulated renin secretion. This inhibitory effect is not restricted to a specific pathway of stimulation because it not only affected renin secretion stimulated by beta -adrenoreceptor activation but also attenuated stimulation by inhibition of macula densa salt transport with bumetanide and by a drop in the renal artery pressure. This inhibitory effect of the Ca2+-ATPases was calcium dependent because thapsigargin failed to suppress isoproterenol-stimulated renin secretion when extracellular calcium concentrations were low. In addition, lowering extracellular calcium into the submicromolar range by adding EGTA immediately reversed thapsigargin-induced renin suppression. Given a specific effect of the Ca2+-ATPase inhibitors on renin secretion that is related to calcium, then their effects on renin secretion could be due either to an accumulation of cytosolic calcium, which cannot flow off into internal stores, or to an activation of calcium influx from outside, triggered by a signal related to the filling state of internal calcium stores. The observation that the inhibitory action of Ca2+-ATPase inhibitors on renin secretion was almost instantaneously abolished by a lowering of the extracellular calcium concentration supports the conclusion that it is the calcium influx from outside that primarily mediates the inhibitory action of Ca2+- ATPase blockers on renin secretion.

We infer from these findings, that a significant store-operated calcium influx exists in renal juxtaglomerular cells and that activation of this influx represents a powerful inhibitory signal for renin secretion. Both conclusions are in good accordance with previous findings. Thus we have reported previously that angiotensin II mobilizes calcium from internal stores in juxtaglomerular cells and transiently increases the calcium permeability of the plasma membrane, what would be compatible with store-regulated calcium influx (17). Furthermore, it is well known that the inhibitory action of angiotensin II on renin secretion is strongly dependent on extracellular calcium, compatible with an inhibition of renin secretion by store-operated calcium influx (1, 39).

The results of our study, moreover, suggest that the store-regulated calcium influx into renal juxtaglomerular cells does not follow the well-characterized pathway of store-operated calcium influx, which can be blocked by lanthanum, gadolinium, or flufenamic acid (13, 28, 32). L-type calcium channels do not appear to play a role in mediating the effects of thapsigargin on the renin-secretion either, as amlodipine failed to reverse its suppression mediated by thapsigargin. Alternative ways for calcium influx include the recently identified more unspecific cation channels that are also activated by depletion of internal calcium stores (21, 38, 41) and calcium-activated calcium channels that are store independent and have been detected in a large variety of cells (16, 22, 40).

A further interesting result of our study is that the only moderate attenuation of perfusate flow by thapsigargin and cyclopiazonic acid indicating that inhibition of endoplasmatic reticulum Ca2+-ATPase has only minor effects on the contractility of renal resistance vessels in our experimental model. Although the renal vascular resistance is set on a rather low level in the isolated perfused kidney model compared with the in vivo situation and the interpretation of the perfusate flow changes might therefore be limited, it has been shown several times that vasoconstrictors like angiotensin II mediate a dose-dependent vasoconstriction in our model (30, 35). Therefore, it can be speculated from our results that internal calcium stores and calcium release-activated calcium channels are not the main regulatory step in the control of vascular tone of renal resistance vessels. Our results are in good accordance with a recent study showing thapsigargin not altering diameters of afferent and efferent arterioles of isolated perfused hydronephrotic kidneys under basal conditions (35). Furthermore, our data support previous findings that angiotensin II-induced calcium influx mediating vasoconstriction of resistance vessels and suppression of renin secretion in juxtaglomerular cells follows to different pathways. Although we and others found a marked effect of L-type Ca2+-channel blockers on regulation of vascular tone (5, 20, 30), we found no attenuation of renin secretion (30). As mentioned above, we could not find evidence for a role for voltage-operated calcium channels in juxtaglomerular cells (19) but in more proximal smooth muscle cells of afferent arterioles (31).

In conclusion, our data show a marked inhibitory effect on renin secretion by inhibition of the endoplasmatic Ca2+-ATPase. Instantaneous reversal of this inhibition by lowering extracellular calcium concentration into the submicromolar range suggests that a calcium influx from the extracellular space is responsible for this inhibition. Store-operated calcium channels do not appear to be a main regulatory step for the contractility of renal resistance vessels, because inhibition of endoplasmatic Ca2+-ATPase attenuated perfusate flow only slightly. Together, these results emphasize our previous findings that calcium influx in juxtaglomerular cells and renal smooth muscle cells mediating suppression of renin secretion and vasoconstriction follow different pathways.


    ACKNOWLEDGEMENTS

This study was financially supported by the Deutsche Forschungsgemeinschaft (Ku 859/2-3).


    FOOTNOTES

Address for reprint requests and other correspondence: F. Schweda, Institut für Physiologie I, Universität Regensburg, 93040 Regensburg, Germany (E-mail: frank.schweda{at}klinik.uni-regensburg.de).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Received 17 August 1999; accepted in final form 1 March 2000.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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