(Hypertension. 1995;25:1025-1029.)
© 1995 American Heart Association, Inc.
Articles |
Role of Endogenous Endothelins in the Renin System of Normal and Two-Kidney, One Clip Rats
From the Physiologisches Institut der Universität Regensburg (Germany) (K.S., H.S., M.H., A.K.); F. Hoffmann–La Roche Ltd, Basel, Switzerland (M.C.); and the Klinik und Poliklinik für Innere Medizin II, Universität Regensburg (Germany) (B.K.K.).
Correspondence to Dr Karin Schricker, Institut für Physiologie I, Universität Regensburg, Postfach 101042, 93040 Regensburg, FRG.
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Abstract |
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Abstract This study aimed to investigate the relevance of endogenous endothelins in the control of renin secretion and renin gene expression under basal conditions and stimulated conditions achieved with unilateral renal artery stenosis. To this end, we studied the effects of the orally active endothelin antagonist Ro 47-0203 (100 mg/kg per day) for 2 days on plasma renin activity and renal renin mRNA levels in normal rats and rats with unilateral renal artery clips (0.2 mm). Treatment with Ro 47-0203 did not change basal arterial pressure but significantly attenuated the rise of blood pressure in response to renal artery clipping. Although Ro 47-0203 tended to increase basal plasma renin activity, this effect was not significant. Basal renin mRNA levels of kidneys were also not changed by the drug. Unilateral renal artery clipping increased plasma renin activity from 12 to 34 ng angioten-sin I/mL per hour, increased renin mRNA levels to 328% of controls in the clipped kidneys, and decreased renin mRNA levels to 23% of controls in the contralateral intact kidneys. These changes were not influenced by Ro 47-0203. In isolated perfused rat kidneys, Ro 47-0203 (10 µmol/L) also had no effect on basal renin secretion or vascular resistance, but it substantially attenuated the decrease of renin secretion and renal flow in response to administration of exogenous endothelin. Taken together, these findings suggest that endogenous endothelins play no relevant role in the control of renin secretion and of renin gene expression in normal and hypoperfused rat kidneys.
Key Words: blood pressure • juxtaglomerular cells • endothelium • endothelins • renin
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Introduction |
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Evidence is accumulating that endothelial mediators regulate renin expression and secretion in renal juxtaglomerular cells. In vivo and in vitro findings suggest that prostacyclin, the main cyclooxygenase product of endothelial cells, stimulates renin secretion from juxtaglomerular cells.1 2 Moreover, the endothelium-derived relaxing factor appears to be required for the stimulation of renin secretion induced by a reduction of renal perfusion pressure.3 4 5 There is also evidence that a third group of endothelial factors, namely, endothelins, can modulate renin secretion. The findings about the effects of endothelins on renin secretion, however, are controversial and may depend on the experimental model used. Thus, endothelins have been reported to inhibit basal or stimulated renin secretion in anesthetized dogs,6 7 isolated perfused rat kidneys,8 kidney slices,9 10 11 isolated glomeruli,12 and isolated juxtaglomerular cells.10 13 14 On the other hand, findings have indicated a stimulation of renin secretion by endothelin in anesthetized dogs,15 blood vessels,16 and decidual cells.17 It has been reported furthermore that endothelin may either inhibit or stimulate renin secretion in anesthetized rats depending on the dose applied.18
All of these studies used the pharmacological approach of adding exogenous endothelins, which may imply specific problems and may therefore account for the different results. For instance, the concentration of exogenous endothelins used may be out of the range occurring physiologically at the respective site of action. Also, a general and long-lasting increase of the extracellular concentration of endothelins may cover particular physiological effects resulting from locally and timely restricted release of endogenous endothelin. To address the physiological effect and relevance of endothelins on the renin system, we thought it reasonable to use a complementary approach and study the effects on the renin system that result from the inhibition of endogenous endothelin in vivo. In this context, we were interested in examining the effect of endothelin inhibition on renin secretion and renal renin gene expression under basal and stimulated conditions. To stimulate the renin system, we used unilateral renal artery clipping, which leads to an increase of renin secretion and renin gene expression in the stenosed kidney and to a suppression of renin gene expression in the contralateral intact kidney.19 At the same time, kidney hypoperfusion increases endothelin-1 mRNA levels after short-term ischemia.20 To inhibit endogenous endothelin activity, we used the newly developed and orally active endothelin antagonist Ro 47-0203.21 This compound antagonizes the effects of all endothelin subtypes and is more effective than the recently described compound Ro 46-2005.22 Our findings show that Ro 47-0203 has no significant effects on renin secretion and renin gene expression either in normal rats or in rats with unilateral renal artery clips.
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Methods |
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Animals
Four groups of male Sprague-Dawley rats having free access to standard chow (Altromin, Feldkirchen-Heimstetten) and tap water were used. Group 1 and 2 rats received vehicle (gummi arabicum) or Ro 47-0203 (100 mg/kg) by gastric gavage at the beginning of the experiments and 20 and 44 hours later. Group 3 and 4 rats were anesthetized with methohexital (75 mg/kg IP), and the left kidneys were exposed by abdominal incision. Sterile silver clips (0.2-mm ID, Degussa AG) were then placed on the left renal arteries. Thirty minutes after the rats had regained consciousness, they were fed with vehicle or Ro 47-0203 (100 mg/kg) by gastric gavage. Vehicle and drug were given again 20 and 44 hours later.
Rats were killed by decapitation 2 hours after the last administration of vehicle or drug. Blood was sampled from the carotid arteries, immediately anticoagulated with EGTA, and centrifuged. The obtained plasma was stored at -20°C until assay of plasma renin activity (PRA). The kidneys were rapidly removed, weighed, frozen in liquid nitrogen, and stored at -80°C until isolation of RNA.
Blood Pressure Measurement
Systolic blood pressure of the conscious rats was measured with
the tail-cuff method using a blood pressure recorder (model 8005,
Rhema). Blood pressure measurements were made before experiments were
started and 14 hours and 1 hour before animals were killed.
Determination of Preprorenin mRNA
Total RNA was extracted from the kidneys, which were stored at
-70°C, according to the protocol of Chomczynski and
Sacchi23 by homogenization in 10 mL of solution D (4 mol/L
guanidine thiocyanate containing 0.5% N-lauryl-sarcosinate,
10 mmol/L EDTA, 25 mmol/L sodium citrate, and 700 mmol/L
ß-mercaptoethanol) with a polytron homogenizer. Then, 1 mL sodium
acetate (2 mol/L, pH 4), 10 mL phenol (water saturated), and 2 mL
chloroform were added sequentially to the homogenate, with thorough
mixing after addition of each reagent. After cooling on ice for 15
minutes, samples were centrifuged at 10 000g for 15 minutes
at 4°C. RNA in the supernatant was precipitated with an equal volume
of isopropanol at -20°C for at least 1 hour. After centrifugation,
RNA pellets were resuspended in 0.5 mL of solution D, again
precipitated with an equal volume of isopropanol at -20°C, and
finally dissolved in diethylpyrocarbonate-treated water and stored at
-80°C until further processing. Renin mRNA was measured by RNase
protection as described previously.24 A preprorenin cRNA
probe containing 296 bp of exons I and II, generated from a pGEM-4
vector carrying a Pst I–Kpn I restriction
fragment of a rat preprorenin cDNA,25 was generated by
transcription with SP6 RNA polymerase (Amersham International).
Transcripts were continuously labeled with [
-32P]GTP
(410 Ci/mmol, Amersham) and purified on a Sephadex G50 spun column. For
hybridization, total kidney RNA was dissolved in a buffer containing
80% formamide, 40 mmol/L
piperazine-N,N'-bis(2-ethane sulfonic
acid) (PIPES), 400 mmol/L NaCl, and 1 mmol/L EDTA (pH 8). RNA (20 µg)
was hybridized in a total volume of 50 µL at 60°C for 12 hours with
5x105 cpm radiolabeled renin probe. RNase digestion with
RNase A and T1 was carried out at 20°C for 30 minutes and terminated
by incubation with proteinase K (0.1 mg/mL) and sodium dodecyl sulfate
(0.4%) at 37°C for 30 minutes. Protected preprorenin mRNA fragments
were purified by phenol/chloroform extraction, ethanol precipitation,
and subsequent electrophoresis on a denaturing 10% polyacrylamide gel.
After autoradiography of the dried gel at -70°C for 1 to 2 days,
bands representing protected renin mRNA fragments were excised
from the gel, and radioactivity was counted with a liquid scintillation
counter (1500 Tri-Carb, Packard Instrument Co). The number of counts
per minute obtained from each sample of total kidney RNA was expressed
relative to an external renin mRNA standard included in each
hybridization consisting of 20 µg pooled RNA extracted from the 12
kidneys of six normal Sprague-Dawley rats.
Determination of Actin mRNA
The abundance of rat cytoplasmatic ß-actin mRNA in total
RNA isolated from the kidneys was determined by RNase protection assay
as described previously.24 An actin cRNA probe containing
the 76-nucleotide first exon and approximately 200 bp of surrounding
sequence was generated by transcription with SP6 polymerase from a
pAM19 vector carrying an Ava I–HindIII
restriction fragment of actin cDNA. For one assay, 2.5 µg RNA was
hybridized under the conditions described for the determination of
renin mRNA.
Renin Secretion Studies With Isolated Perfused Rat Kidneys
Experiments with isolated perfused rat kidneys were performed as
described in detail previously.26 In brief, male (250 to
350 g) Sprague-Dawley rats (Charles River, Sulzfeld, Germany)
with free access to a normal sodium diet and tap water were used
throughout. The animals were anesthetized with 150 mg/kg
5-ethyl-(1'-methyl-propyl)-2-thio-barbituric acid (Inactin,
Byk-Gulden). Volume loss during the preparation was corrected by
intermittent injections of physiological saline (approximately 2.5 mL
total) through a catheter inserted into the jugular vein. After the
abdominal cavity had been opened by a midline incision, the right
kidney was exposed and placed in a thermoregulated metal chamber. After
heparin injection (2 IU/g IV, Braun), the aorta was clamped distal to
the right renal artery, and the large vessels branching off the
abdominal aorta were ligated. A double-barreled cannula was inserted
into the abdominal aorta and placed close 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. The kidney was excised,
and perfusion at constant pressure (80 mm Hg) was established. Renal
artery pressure was monitored by a strain-gauge transducer (P23Db,
Statham), and the pressure signal was used for feedback control of a
peristaltic pump. The perfusion circuit was closed by draining the
renal venous effluent through a metal cannula back into a reservoir
(200 to 220 mL). The basic perfusion medium, which was taken from the
thermostated (37°C) reservoir, consisted of a modified
Krebs-Henseleit solution containing (mmol/L) Na+ 140,
K+ 5.0, Ca2+ 1.25,
Mg2+ 2.0, Cl- 120,
HCO3- 27.5, and
HPO42- 0.7. The perfusate was enriched with
all physiological amino acids in concentrations between 0.2 and 2.0
mmol/L and contained in addition (mmol/L) glucose 8.7, pyruvate 0.3,
L-lactate 2.0, -ketoglutarate 1.0,
L-malate 1.0, creatinine 0.15, and urea 6.0, as well as 6
g/100 mL bovine serum albumin, 1 mIU/100 mL vasopressin 8-lysine, and
freshly washed human red blood cells (10±2% hematocrit). Ampicillin
(3 mg/100 mL) and flucloxacillin (3 mg/100 mL) were added to inhibit
bacterial growth. To improve the functional preservation of
preparations, the perfusate was continuously dialyzed against a 25-fold
volume of medium of similar composition but without erythrocytes and
albumin. For oxygenation of the perfusion medium, the dialysate was
equilibrated with prewarmed and moistened gas consisting of a 94%
oxygen/6% carbon dioxide mixture. Perfusate flow rates were determined
from the revolutions of the peristaltic pump, which was calibrated
before each experiment. Renal flow rate and perfusion pressure were
continuously monitored by a potentiometric recorder (REC 102, Pharmacia
LKB). Stock solutions of endothelin and Ro 47-0203 were dissolved in
freshly prepared dialysate and infused into the arterial limb of the
perfusion circuit directly before the kidneys at exactly 1% of the
rate of perfusate flow (perfusor adapted from Fresenius). For
determination of perfusate renin activity, aliquots (approximately 0.2
mL) were taken at 2-minute intervals from the arterial limb of the
circulation and the renal venous effluent, respectively. Samples were
centrifuged (4°C) at 1500g for 15 minutes in a benchtop
centrifuge (Eppendorf 5413), and the supernatants were subsequently
assayed for PRA using the plasma from bilaterally nephrectomized rats
as renin substrate.
PRA was determined with the use of a commercially available radioimmunoassay kit for angiotensin I (Ang I) (Sorin Biomedica).
Statistics
Levels of significance were determined by ANOVA for
interindividual comparisons and by paired Student's t test
for intraindividual comparisons. Values are mean±SEM.
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Results |
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Treatment of rats with the endothelin antagonist Ro 47-0203 did not change body mass or kidney weights when compared with weights of vehicle-fed rats (225±4.3 and 1.07±0.009 g, respectively, n=5).
In unclipped rats, Ro 47-0203 did not change systolic blood pressure (Fig 1, top) and tended to increase PRA from 12±3 to 17±3 ng Ang I/mL per hour (n=5; Fig 2, top). However, this increase was not statistically significant. Clipping of the left renal arteries with 0.2-mm clips led to an increase of systolic blood pressure from 120±4 to 157±4 mm Hg (n=8) in vehicle-fed rats after 2 days (Fig 1, bottom). This increase of blood pressure in response to clipping was attenuated by Ro 47-0203 to 141±6 mm Hg (n=8; Fig 1, bottom). Clipping also increased PRA from 12±3 to 34±10 ng Ang I/mL per hour (n=8) in vehicle-fed rats (Fig 2, bottom), but this increase was not changed by Ro 47-0203 (37±9 ng Ang I/mL per hour, n=8).
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Renin mRNA levels in the kidneys were determined by an RNase protection assay using total RNA pooled from the kidneys of normal rats as an external standard. Fig 3 shows an autoradiograph of a representative renin RNase protection assay for the kidneys of clipped vehicle-treated, clipped Ro 47-0203–treated, unclipped vehicle-treated, and unclipped Ro 47-0203–treated rats. This autoradiograph suggests that Ro 47-0203 has no major effect on renin mRNA levels in unclipped or clipped rats. Analysis of all rats did indeed reveal no effect of Ro 47-0203 on renal renin mRNA levels in unclipped rats (Fig 4, top). Also, characteristic changes of renal renin mRNA levels in response to unilateral renal artery clipping were not influenced by Ro 47-0203. Left renal artery clipping increased renin mRNA levels to 328±26% and 315±23% (n=8) of controls in the clipped kidneys and decreased renin mRNA levels to 23±9% and 30±11% (n=8) of controls in the contralateral intact kidneys in the absence and presence of Ro 47-0203, respectively (Fig 4, bottom).
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To test for the efficacy of RNA extraction from the kidneys, we also analyzed the abundance of cytoplasmic ß-actin mRNA in the total RNA isolated from the kidneys. We found that neither clipping nor treatment with the endothelin antagonist changed the abundance of actin mRNA in the kidneys (data not shown).
To examine whether Ro 47-0203 is capable of influencing the interaction between endothelins and the renin system, we investigated its effects on renin secretion and renal vascular resistance in isolated rat kidneys. Kidneys were perfused with a constant pressure of 80 mm Hg, and increasing concentrations of endothelin-1 were added in the absence and presence of Ro 47-0203. In these experiments, we found that endothelin-1 produced dose-dependent decreases of basal flow rates and basal renin secretion rates (Fig 5). Continuous infusion of Ro 47-0203 into the perfusate at a concentration of 10 µmol/L did not change basal flow rates or basal renin secretion rates but significantly attenuated the vasoconstriction and inhibition of renin secretion produced by endothelin-1.
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Discussion |
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We undertook this study to determine the role of endogenous endothelins on renin secretion and renin gene expression. We used an orally active endothelin antagonist that has been found to have a long-lasting action and that antagonizes the effects of endothelin-1, endothelin-2, and endothelin-3 in rats.21 The dosage of 100 mg/kg per day was chosen because previous studies in rats21 showed that this dose produces maximal effects. In accordance with previous findings, we obtained no evidence for substantial and physiologically relevant side effects of the drug, as suggested by the normal body and kidney weights of the rats receiving it. The observation that Ro 47-0203 did not change basal systolic blood pressure (Fig 1, top) is also in keeping with a previous study that reported no effect of Ro 47-0203 on blood pressure in normotensive rats.27 On the other hand, our finding that Ro 47-0203 significantly attenuated the development of hypertension upon renal artery stenosis (Fig 1, bottom) contradicts the study of Clozel et al27 but fits well with a reduction of blood pressure in other forms of hypertension.27
Renin secretion rates as reflected by PRA tended to increase in unclipped rats during treatment with the endothelin antagonist (Fig 2, top), suggesting that any effect of endogenous endothelins on renin secretion is an inhibitory one. This finding would fit with a number of in vivo and in vitro demonstrations that exogenous endothelin inhibits renin secretion (Fig 5).6 7 8 9 10 11 12 13 14 However, at the same time, our findings suggest that endogenous endothelin is not relevant for the control of renin secretion and renin gene expression in kidneys under normal conditions.
To examine whether endogenous endothelins play a role in regulating the renin system under conditions stimulated with regard to both renin and endothelin, we used unilateral renal artery clipping. In accordance with previous studies,19 28 29 30 31 we found that clipping markedly stimulated renin secretion and renin mRNA levels in the clipped kidneys (Fig 2, bottom; Fig 4, bottom). Moreover, we suppose from findings of Firth and Ratcliffe20 that endothelin-1 mRNA levels were increased after renal hypoperfusion. Again, the endothelin antagonist Ro 47-0203 was without effect on renin secretion and renal renin gene expression in these rats (Fig 2, bottom; Fig 4, bottom).
Given the facts that the endothelin antagonist was administered at a sufficiently high dose, according to Clozel et al21 and as indicated by the Ro 47-0203–induced reduction of hypertension in our experiments, and that administration of exogenous endothelins influences renin secretion in vivo and in vitro,6 7 8 9 10 11 12 13 14 15 16 17 18 there may be two main reasons for the lack of effect of the endothelin antagonist Ro 47-0203 in our study. Either the effects of endothelins on renal juxtaglomerular cells are mediated by a novel subtype of endothelin receptors that are not antagonized by Ro 47-0203, or the effective concentrations of endogenous endothelins in the surrounding juxtaglomerular cells are too low to be effective under both basal and stimulated conditions. In view of the observation that Ro 47-0203 did in fact antagonize the effects of exogenous endothelin on renin secretion in the isolated perfused kidney, we consider the first possibility as the less likely explanation. Therefore, we would infer from our results that endogenous endothelin is not a physiologically relevant regulator of the intrarenal renin system in normal and hypoperfused kidneys. This conclusion is also supported by the observation that the endothelin antagonist did not change basal renin secretion in the isolated perfused kidney.
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Acknowledgments |
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This study was supported by a grant from the Deutsche Forschungsgemeinschaft (Ku 859/2-1). The expert technical and graphical assistance provided by Karl-Heinz Götz and Marie-Luise Schweiger and the secretarial help provided by Hannelore Trommer are gratefully acknowledged.
Received July 12, 1994; first decision August 16, 1994; accepted December 15, 1994.
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H. Ehmke, J. Faulhaber, K. Munter, M. Kirchengast, and R. J. Wiesner Chronic ETA Receptor Blockade Attenuates Cardiac Hypertrophy Independently of Blood Pressure Effects in Renovascular Hypertensive Rats Hypertension, April 1, 1999; 33(4): 954 - 960. [Abstract] [Full Text] [PDF]
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 W. G. Haynes, C. J. Ferro, D. J. Webb, B. K. Kramer, F. Schweda, G. A.J. Riegger, H. Krum, Y. Lacourciere, and V. Charlon Bosentan in Essential Hypertension N. Engl. J. Med., July 30, 1998; 339(5): 346 - 347. [Full Text]
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A. Herizi, B. Jover, N. Bouriquet, and A. Mimran Prevention of the Cardiovascular and Renal Effects of Angiotensin II by Endothelin Blockade Hypertension, January 1, 1998; 31(1): 10 - 14. [Abstract] [Full Text] [PDF]
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L. V. d'Uscio, P. Moreau, S. Shaw, H. Takase, M. Barton, and T. F. Luscher Effects of Chronic ETA-Receptor Blockade in Angiotensin II-Induced Hypertension Hypertension, January 1, 1997; 29(1): 435 - 441. [Abstract] [Full Text] [PDF]
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J.-S. Li, L. Y. Deng, K. Grove, C. F. Deschepper, and E. L. Schiffrin Comparison of Effect of Endothelin Antagonism and Angiotensin-Converting Enzyme Inhibition on Blood Pressure and Vascular Structure in Spontaneously Hypertensive Rats Treated With N{omega}-Nitro-L-Arginine Methyl Ester: Correlation With Topography of Vascular Endothelin-1 Gene Expression Hypertension, August 1, 1996; 28(2): 188 - 195. [Abstract] [Full Text]
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