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(Hypertension. 1995;26:733.)
© 1995 American Heart Association, Inc.

Articles

Renin and Angiotensin II Receptor Gene Expression in Kidneys of Renal Hypertensive Rats

Jacques-Antoine Haefliger¹; Gabriela Bergonzelli¹; Gérard Waeber; Jean-François Aubert; Jürg Nussberger; Haralambos Gavras; Pascal Nicod; Bernard Waeber

From the Department of Internal Medicine B (J.-A.H., G.B., G.W., P.N.) Centre Hospitalier Universitaire Vaudois, the Division of Hypertension (J.-F.A., J.N., B.W.), Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, and the Hypertension Section (H.G.), Boston University Medical Center, Boston, Mass.

Correspondence to J.-A. Haefliger, PhD, Laboratory of Molecular Biology 19-521, Department of Internal Medicine B, Centre Hospitalier Universitaire Vaudois, CHUV—1011 Lausanne, Switzerland.

	Abstract

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Abstract The aim of this investigation was to examine the interrelation between renal mRNA levels of renin and angiotensin II receptor type 1 (AT₁) in a renin-dependent form of experimental hypertension. Rats were studied 4 weeks after unilateral renal artery clipping. Mean blood pressure and plasma renin activity were significantly higher in the hypertensive rats (n=10 206±8 mm Hg and 72.4±20.9 ng · mL^-1 · h^-1, respectively) than in sham-operated controls (n=10, 136±3 mm Hg and 3.3±0.5 ng · mL^-1 · h^-1, respectively). Northern blot analysis of polyA⁺ RNA obtained from the kidneys of renal hypertensive rats showed increased levels of renin mRNA in the clipped kidney, whereas a decrease was observed in the unclipped kidney. Plasma renin activity was directly correlated with renin mRNA expression of the poststenotic kidney (r=.94, P<.01). AT₁ mRNA expression was lower in both kidneys of the hypertensive rats. This downregulation was specific for the AT_1A subtype since the renal expression of the AT_1B subtype remained normal in hypertensive rats. The downregulation of the renal AT_1A receptor may be due to high circulating angiotensin II levels. This is supported by the significant inverse correlation (r=-.71, P<.01) between plasma renin activity and AT_1A mRNA expression measured in the clipped kidney of the hypertensive rats.

Key Words: renin • RNA, messenger • blood pressure • renovascular hypertension • receptors, angiotensin

	Introduction

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Reducing blood flow to the kidney by constricting the irrigating renal artery, with the contralateral kidney untouched, produces a sustained elevation of blood pressure.¹ In rats, this experimental type of hypertension, known as the 2K1C model of renal hypertension, is established to be renin dependent. Thus, renin secretion stimulated on the side of the renal artery stenosis leads to a rise in PRA.² Inhibition of the renin-angiotensin system with angiotensin-converting enzyme inhibitors or Ang II receptor antagonists can prevent the development of hypertension in these rats.^{3 4} These drugs also are able to reverse hypertension in rats having chronically elevated blood pressure.^{5 6 7}

The renin release triggered by hypoperfusion of the stenosed kidney leads to an enhanced generation of Ang II.⁸ This octapeptide, beyond its contractile effect on the vasculature and its stimulatory action on aldosterone secretion from the adrenal glomerulosa, exerts a negative feedback control on renin expression and secretion^{9 10} and is probably the main factor involved in the inhibition of renin expression and secretion from juxtaglomerular cells located in the contralateral, unclipped kidney.^{11 12 13} However, other mechanisms possibly are involved in the attenuation of renin release from the intact kidney, including the elevation of blood pressure per se, the activation of the macula densa by a neuronal mechanism, and/or renorenal reflexes.^{14 15}

The goal of the present study was to investigate the modulation of renal and AT₁ gene expression in renovascular hypertension. Rats were subjected to unilateral renal artery clipping 4 weeks before death (long-term form of 2K1C hypertension). The renal mRNA levels of renin and AT₁ were analyzed. The rat AT₁ receptor has been cloned,¹⁶ localized in the kidneys,¹⁷ and recognized to mediate the known effects of Ang II.¹⁸ In the rat kidney, two subtypes of the AT₁ receptor (AT_1A and AT_1B) have been described; they share 91% nucleic acid sequence identity in their coding region but differ in their 3' untranslated region.^{19 20} We used cDNA probes that specifically recognized AT_1A or the AT_1B.

	Methods

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Animal Experiments
The procedures followed in the care and euthanasia of the rats were approved by the institutional review committee for animal experiments. Two groups of male normotensive Wistar rats (Iffa Credo, L’Arbresles, France) weighing 140 to 180 g were used. Twelve rats were anesthetized with halothane (Halothane BP, Arovet AG) and had the left renal artery clipped by placement of a solid U-shaped silver clip with a 0.2-mm ID (2K1C rats). Twelve additional rats underwent a sham operation, in which an incision was made in the left flank to expose the kidney and the renal artery without clipping the vessel (sham-operated rats). The animals were then returned to their cage and kept on a regular diet containing 0.27% NaCl (Indulab) for 4 weeks. They were housed in a conditioned environment with temperature and humidity remaining constant and light/dark cycles. The rats had free access to tap water. Twenty-four hours before death, they were operated on under light halothane anesthesia to allow the insertion of arterial (right internal iliac artery) and venous (right femoral vein) catheters. The catheters (PE-10, Portex) were exteriorized between the scapulae and filled with a heparinized 0.9% NaCl solution. The rats were then placed in individual cages for 24 hours to recover from anesthesia. On the day of the experiment, the rats were installed in a plastic tube to restrict their movement. Intra-arterial pressure and heart rate were recorded continuously with a data acquisition system.²¹ After a 2-hour baseline period to stabilize hemodynamic parameters, a 2-mL blood sample was obtained through the arterial line for measurement of PRA. The blood was collected in EDTA-coated tubes and centrifuged immediately at 4°C. The plasma samples were stored at -70°C until assayed, using a previously described method.²² Immediately thereafter, the animals were killed with an overdose of methohexital. Diethyl pyrocarbonate (50 mL) (Sigma) in phosphate-buffered saline was rapidly perfused through the left ventricle, and the kidneys were removed and weighed.

RNA Isolation From Kidneys
The kidneys were homogenized in 9 mL of 4-mol/L guanidine hydrothiocyanate buffer using a Kinametic Polytron blender (Kriens) and layered onto a 4-mL 5.7-mol/L CsCl cushion. Total RNAs were pelleted by ultracentrifugation at 33 000 rpm for 20 hours in a 50-Ti rotor. PolyA⁺ RNA was obtained by affinity chromatography on oligo[dT(+)] cellulose (Calbiochem-Novabiochem AG) as previously described.²³

Northern Blot Analysis
PolyA⁺ RNA (4 µg) was size-fractionated on 1% agarose gels containing 8% formaldehyde (Fluka) and 1x MOPS buffer (Fluka). Gels were transferred by capillary blotting (10x SSC) to Gene Screen membranes (Du Pont). Membranes were UV cross-linked and vacuum-baked for 2 hours at 80°C. mRNA levels were determined by hybridization by random-primed (Boehringer Mannheim) with [-³²P]dCTP (Amersham). Overnight hybridization was in 5x SSPE, 50% formamide, 5x Denhardt’s solution, 5% SDS, and 100 µg/mL purified salmon sperm DNA at 42°C. The blots were washed three times at 42°C for 10 minutes in 2x SSC, 1% SDS and three times for 20 minutes each in 0.1x SSC, 1% SDS. Exposure times of all membranes to x-ray film (X-Omat AR, Kodak) were chosen to optimize the signals in the linear range. To correct for variations in the amount of polyA⁺ RNA loaded in each lane, Northern blots were rehybridized with the ubiquitously expressed gene GAPDH.

DNA Probes
The probes used were the 0.7-kb EcoRI insert of rat renin cDNA¹² ; the 1.1-kb (HindIII-EcoRI) fragment of GAPDH cDNA,²⁴ the 0.9-kb (Sac 1-BamHI) fragment of the rat AT_1A cDNA,¹⁶ and the 0.8-kb (HindIII) fragment of the rat AT_1B cDNA.²³

Data Analysis
Densitometric analysis of mRNA signals on autoradiograms was performed with a Molecular Dynamics scanner (Sunnyvale). Densitometric values represent the integration of the area and are corrected for the baseline background reading. The ratio of the specific and the corresponding GAPDH signal was determined and expressed relative to the minimum value to which an arbitrary score of 1 was assigned.

Data are expressed as mean±SEM. Mean blood pressure, heart rate, body weight, kidney weight, and PRA were statistically analyzed using one-way superANOVA followed by Scheffé’s test. For the Northern blot analysis, relative mRNA levels were calculated and then statistically compared using superANOVA and Fisher’s least significant difference test. The correlation coefficients were calculated by linear regression. Statistical significance was defined at values of P<.05, P<.01, and P<.001.

	Results

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The characteristics of the two study groups (sham; 2K1C) are given in the Table. There was no significant difference in body weight and heart rate between the two groups of rats. The 2K1C animals exhibited significantly increased blood pressures (P<.001) compared with sham-operated controls. Hypertension was associated with significantly higher values of PRA (P<.05). The right kidney weighed significantly more (P<.001) in 2K1C rats than in controls, but there was no significant difference between the clipped left kidney of the hypertensive animals and the left kidney of the sham-operated rats.

View this table: [in this window] [in a new window]   Table 1. Characteristics of the 2K1C and Sham-Operated (Sham) Rats (n=10)

Renal Renin Gene Expression
Fig 1a illustrates typical Northern blots of kidney PolyA⁺ RNA obtained from four 2K1C and four sham-operated rats with a renin cDNA probe. An increased level of renin mRNA in the clipped kidney of the 2K1C renal hypertensive rats was observed, whereas the mRNA levels in the contralateral kidney were significantly lower. No difference was seen between the two kidneys of the control rats. The same blots were subsequently hybridized with a GAPDH cDNA probe to allow a precise quantitative assessment of renin expression normalized to the GAPDH gene expression.

View larger version (31K): [in this window] [in a new window]   Figure 1. a, Renin gene expression. Northern blots of kidney polyA+ RNA of four 2K1C renal hypertensive rats and four sham-operated controls (Sham) hybridized with renin and GAPDH cDNA probes. b, Bar graph shows quantitative assessment of renin and GAPDH mRNA expression in the left kidney (LK) and the right kidney (RK) of 10 2K1C renal hypertensive rats and sham-operated controls (Sham). **P<.01, ***P<.001 vs Sham.

Fig 1b shows the quantitative assessment of renin polyA⁺ RNA expression in both kidneys of the two groups of 10 rats. In 2K1C hypertensive rats, renin mRNA levels were markedly higher (250%) in the clipped left kidney (P<.001) compared with the contralateral kidney. It was also significantly increased (P<.001) in comparison with the kidneys obtained from sham-operated rats. Renin mRNA levels were decreased by 36% in the unclipped right kidney of the hypertensive rats compared with the right kidney of sham-operated animals (P<.01).

There was a close relationship in 2K1C hypertensive rats between renin mRNA expression measured in the clipped left kidney and PRA (r=.94, P<.01) (Fig 2). In the left kidney of sham-operated rats, the coefficient of correlation between the two parameters was r=.71 (P<.01).

View larger version (17K): [in this window] [in a new window]   Figure 2. Graph shows linear relationship between renin mRNA expression in the clipped kidney and PRA measured in 2K1C renal hypertensive rats. The results obtained in the left kidney of sham-operated rats (Sham) are also shown.

AT_1A and AT_1B Receptor Subtypes Gene Expression in Kidneys
Northern blots containing 10 µg of normotensive rat kidney polyA⁺ RNA were hybridized with AT_1A or AT_1B cDNA probes. As shown in Fig 3, the AT_1A transcript is more abundant than the AT_1B mRNA. Quantitative assessment of the expression of both receptor subtypes shows an eightfold-higher increase in expression of the AT_1A versus the AT_1B. The size of both transcripts (2.3 kb) is similar. To quantify the expression of the two AT₁ subtype transcripts in the kidney of the 2K1C hypertensive rats, we used the specific AT_1A or AT_1B probe.

View larger version (39K): [in this window] [in a new window]   Figure 3. Northern blots show discrimination of the AT1A and AT1B receptor subtypes. Two lanes of kidney polyA+ RNA (10 µg) were hybridized separately with either the rat AT1A cDNA or the rat AT1B cDNA probes. AT1A mRNA expression is eightfold more abundant than the AT1B transcript. Exposure times are AT1A, 20 hours; AT1B, 3 days.

Fig 4a shows the results obtained after hybridization with the AT_1A probe of kidney polyA⁺ RNA from four representative 2K1C hypertensive rats and four sham-operated controls. Blots were stripped and rehybridized with the GAPDH probe as internal control.

View larger version (34K): [in this window] [in a new window]   Figure 4. a, AT1A mRNA levels. Northern blots hybridized with the AT1A receptor subtype and the GAPDH cDNA probes in left (LK) and right (RK) kidneys of four 2K1C renal hypertensive rats and four sham-operated controls. b, Bar graph shows quantitative assessment of AT1A and GAPDH mRNA expression in the left and the right kidneys of 10 2K1C renal hypertensive rats and 10 sham-operated controls (Sham). *P<.05 vs Sham.

A quantitative analysis of the AT_1A receptor subtype mRNA in the left and the right kidneys of the two groups of 10 animals is given in Fig 4b. The AT_1A receptor mRNA expression was 60% lower in both kidneys of the hypertensive animals compared with the corresponding controls (P<.05).

These Northern blots were subsequently stripped and hybridized with the AT_1B probe. Quantitative assessment of the AT_1B expression demonstrates no difference between the kidneys of the 2K1C or the sham-operated animals (Fig 5).

View larger version (15K): [in this window] [in a new window]   Figure 5. Bar graph shows AT1B mRNA levels; quantitative assessment by autoradiography of AT1B and GAPDH mRNA expression in the left kidney (LK) and the right kidneys (RK) of 10 2K1C renal hypertensive rats and 10 sham-operated controls (Sham).

Fig 6 shows the relationship between AT_1A mRNA expression measured in the left kidney of the 2K1C and sham-operated rats (on the ordinate) and PRA (on the abscissa). There was a significant inverse correlation between the two parameters in hypertensive rats (r=-.71, P<.01) but not in normotensive controls. In the right kidney of 2K1C rats, a significant inverse correlation was also observed (r=-.86, P<.01), whereas no relationship was noted in the right kidney of normotensive rats (not shown).

View larger version (16K): [in this window] [in a new window]   Figure 6. Graph shows inverse relationship between PRA and AT1A mRNA levels in the left kidney of 2K1C renal hypertensive rats and sham-operated controls (Sham). AngI indicates angiotensin I.

Considering the AT_1B mRNA expression and PRA, no significant correlation was seen in hypertensive (r=.39, P=NS) as well as in normotensive (r=.20, P=NS) rats.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The hypertension produced by constricting one renal artery while leaving the contralateral kidney untouched was associated with increased PRA levels. The activation of the renin-angiotensin system observed in this condition is due to the triggering of renin release from the clipped kidney.² This is reflected by enhanced renin mRNA levels in the hypoperfused kidney (Fig 1). Moreover, a direct, close correlation was observed in the hypertensive rats between renin mRNA level in the affected kidney and PRA. The present data were obtained 4 weeks after unilateral renal artery clipping. They are very similar to those reported recently in rats studied during the developmental phase of 2K1C hypertension.¹³ Indeed, 2 weeks after renal artery stenosis was performed, a significant relationship was also observed between renin gene expression in the clipped kidney and PRA. Thus, even in established 2K1C renal hypertension (4 weeks after clipping), the increased PRA reflects stimulated renin mRNA expression of the poststenotic kidney.

Renin secretion is known to be suppressed in the kidney contralateral to the stenosed renal artery. This has been extensively studied in humans with renovascular hypertension. Blood sampling in the renal veins is commonly used to demonstrate lateralization of renin release, which points to a significant involvement of the renal artery stenosis in the pathogenesis of human hypertension.²⁵ Renin release from renal slices is lower in the unclipped than in the clipped kidney of rats with 2K1C hypertension.¹¹ It is now established that the reduced renin release from the intact kidney is associated with decreased renin mRNA levels.^{12 13 15 26} The suppression of renin gene expression manifest in the unclipped kidney of 2K1C renal hypertensive rats is thought to be primarily due to high circulating Ang II levels. This is in agreement with the finding that Ang II downregulates renal renin mRNA expression.^{10 13}

The novel finding of this study is the specific modulation of the renal AT_1A but not AT_1B receptor subtype gene expression. The AT_1A receptor has been cloned in rats and humans.^{16 20} It belongs to the class of G protein–coupled seven-transmembrane receptors and mediates the Ang II effects on the cardiovascular system.¹⁸ In the rat, two different subtypes of the AT₁ receptor exist, the AT_1A and the AT_1B receptors.^{16 20} They are differentially regulated in various organs, including the liver, the adrenal gland, the pituitary gland, and the brain.¹⁹ In the rat kidney, the AT_1A receptor is the predominantly expressed subtype. Whether the AT_1A and AT_1B receptors mediate similar signal transductions in the kidney remains to be elucidated.

Ang II, like other hormones, might be expected to modulate the number of AT₁ receptors. In fact, binding studies performed in 2K1C renal hypertensive rats 7 days after clipping have revealed a reduction of glomerular receptors in the stenosed compared with the intact kidney.²⁷ The present findings provide direct information on the renal gene expression of the AT₁ receptor in rats with a sustained renin-dependent form of hypertension. The probes used made it possible to recognize the AT_1A and AT_1B subtypes. This is noteworthy because distinct responses were seen in the kidneys of our 2K1C rats in terms of mRNA expression of these two subtypes. The AT_1B receptor mRNA was present at lower levels than was the AT_1A receptor mRNA. Moreover, its expression was similar in hypertensive and normotensive rats, with no difference existing between clipped and unclipped kidneys. In contrast, a downregulation of the AT_1A receptor was evidenced in 2K1C renal hypertensive rats. This downregulation was of similar magnitude in both kidneys, which is compatible with the involvement of a circulating factor. A causal relationship between circulating Ang II and the change in AT_1A mRNA expression is suggested by the significant inverse correlation found between PRA and the AT_1A receptor gene expression.

In conclusion, these data confirm that renal renin gene expression is increased in the stenosed kidney and suppressed in the contralateral, nonoperated kidney of rats with established, 2K1C renal hypertension. They also show a different renal gene expression of the two subtypes of the AT₁ receptor, the AT_1A receptor being bilaterally downregulated and the AT_1B being unchanged. The downregulation of the AT_1A receptor expression was inversely correlated with PRA, suggesting a role for Ang II in this gene regulatory response.

	Selected Abbreviations and Acronyms

 

Ang II = angiotensin II AT1 = angiotensin II receptor type 1 GAPDH = glyceraldehyde-3-phosphate dehydrogenase 2K1C = two-kidney, one clip PRA = plasma renin activity

	Acknowledgments

 
This work was supported by grants from the Swiss National Science Foundation (31-3739393 to J.-A.H., 32-3191591 and 32-2931791 to G.W., and 32-033805 to B.W.). J.-A.H. is a recipient of support from the Cloëtta Foundation. The authors would like to thank Dr E. Clauser (Laboratoire de Médecine experimentale, Collège de France, Paris, France) for the generous gift of the AT₁ probes.

	Footnotes

 
¹ Both authors contributed equally to this work.

Received March 24, 1995; first decision May 15, 1995; accepted August 10, 1995.

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