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(Hypertension. 1995;25:674-678.)
© 1995 American Heart Association, Inc.

Articles

Expression of Angiotensin-Converting Enzyme in Renovascular Hypertensive Rat Kidney

Monika Mai; Karl F. Hilgers; Jürgen Wagner; Johannes F. E. Mann; Helmut Geiger

From the Nephrology Laboratory, Department of Medicine IV, University of Erlangen, and Max-Delbrück Center, Berlin-Buch (J.W.), Germany.

Correspondence to Karl F. Hilgers, MD, Child Health Research Center, MR4 Building Room 2001, University of Virginia, Park Place Ln 300, Charlottesville, VA 22908.

	Abstract

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Abstract We hypothesized that the gene expression of angiotensinogen, angiotensin-converting enzyme, and angiotensin II type 1 receptor, in addition to renin, is increased in kidneys after renal artery stenosis. Two-kidney, one clip renovascular hypertension was initiated in Sprague-Dawley rats by clipping of the left renal artery; control rats were sham operated. Blood pressure was not changed for the first 2 days after clipping but was elevated on day 4 (mean arterial pressure, 104±4 versus 87±2 mm Hg in sham-operated control rats, P<.002) and increased further during the next 24 days. Rats were killed 2, 4, 7, 14, and 28 days after clipping or sham operation, and poly(A)⁺-purified renal cortical RNA was analyzed by Northern blotting. Autoradiographs were quantitated by densitometry and normalized for the expression of a housekeeping gene. Renin expression was increased in the clipped kidney (by 149% on day 2) and decreased in the nonclipped kidney (by 82% on day 2), compared with kidneys of control rats. Expression of the angiotensin-converting enzyme was increased in clipped kidneys from the first day after clipping (158%) and throughout the experiment (66% on day 28), but was unchanged or slightly decreased in nonclipped kidneys. Angiotensinogen mRNA showed little change. Angiotensin II type 1 receptor expression was decreased in nonclipped kidneys but unchanged during the first 7 days in clipped kidneys. Our results show that components of the renin-angiotensin system other than renin are also differentially expressed in clipped kidneys. Increased expression of the angiotensin-converting enzyme in poststenotic kidneys occurs very early in the development of renovascular hypertension and may contribute to increased intrarenal angiotensin II formation.

Key Words: hypertension, renovascular • kininase II • receptors, angiotensin • RNA, messenger

	Introduction

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The pivotal role of the renin-angiotensin system (RAS) in the development of renovascular hypertension is well established.¹ In rats, experimental narrowing of one renal artery, with the contralateral kidney left intact, causes hypertension that is mostly, if not entirely, dependent on activation of the RAS.¹ The role of renal renin in this process has been clearly shown: renin secretion and synthesis are stimulated after clipping of the renal artery.^{1 2 3} A marked increase of renin gene expression is detectable as early as 1 day after surgery,² and renin expression in the affected kidney remains elevated even in the chronic stage of two-kidney, one clip (2K1C) hypertension,³ contributing to the maintenance of high blood pressure.

Although renal renin gene expression and its relation to renin release during the onset of 2K1C hypertension have been studied extensively, relatively few data exist on the gene expression of other components of the RAS in the kidney (see "Discussion"). We hypothesized that increased gene expression of other components of the RAS may contribute to increased local angiotensin II (Ang II) formation and effects in the poststenotic kidney. To test this hypothesis, we measured steady-state messenger RNA (mRNA) levels of Ang I–converting enzyme (ACE), angiotensinogen (Aogen), and type 1 Ang II receptor (AT₁) in clipped and nonclipped kidneys during the onset and development of hypertension in 2K1C rats.

	Methods

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Animals
Male Sprague-Dawley rats were obtained from Charles River Wiga and given standard rat chow (Altromin) and tap water ad libitum. All procedures done in animals were performed in accord with the guidelines of the American Physiological Society and were approved by the local government's ethics committee. 2K1C renovascular hypertension was induced when the rats weighed 150 to 180 g, as previously described.⁴ In brief, a 0.20-mm internal diameter silver clip was placed around each rat's left renal artery through a flank incision while the rat was under hexobarbital anesthesia. The right kidney remained untouched. Sham-operated control rats underwent a similar procedure with manipulation of the left renal artery but without permanent application of a clip.

Experimental Protocol
Systolic blood pressure was measured by tail-cuff plethysmography with rats under light ether anesthesia.⁴ The person who performed the measurements was not aware of the group to which each rat belonged. Body weight and systolic blood pressure were measured twice per week and on the day the rats were killed. Four 2K1C and 4 sham-operated rats were instrumented with femoral arterial catheters under hexobarbital anesthesia, as described elsewhere,⁵ 4 days after operation, and the same was done in 10 2K1C and 6 sham-operated animals 19 days after operation. In these rats, direct recordings of arterial blood pressure were obtained while the animals were conscious and moving freely in their usual cages. Blood samples for measurement of plasma renin activity (PRA) and plasma Ang II were obtained from these conscious rats, as described previously.⁶ Plasma Ang II was measured by radioimmunoassay,⁶ and PRA was measured by radioimmunoassay of Ang I⁶ after incubation at 37°C for 1 hour. Five rats from each group (2K1C and sham-operated) were anesthetized with methohexital and killed by exsanguination 2, 4, 7, 14, and 28 days after operation. The heart and both kidneys were quickly excised, and the renal cortices were quickly dissected from the kidneys, cut into small pieces, snap-frozen in liquid nitrogen, and stored at -80°C until RNA was extracted. In a separate experiment, 4 2K1C and 4 sham-operated rats were sacrificed 1 day after clipping for measurement of ACE mRNA.

RNA Extraction and Northern Hybridization
The frozen renal cortical samples were homogenized in cold guanidine isothiocyanate buffer by a motor-driven homogenizer (Ultra-Turrax T25), and the RNA was isolated by a modified acid guanidinium thiocyanate–phenol-chloroform extraction method.⁷ To obtain clear hybridization signals for quantification of low-abundance mRNAs, we used poly(A)⁺-purified rather than total RNA for Northern blot analysis. To get sufficient amounts of total RNA for purification, the total RNA samples were pooled (n=5 from each group). Poly(A)⁺ RNA was purified with an Oligotex-dT mRNA kit (Diagen). Ten micrograms of cortical poly(A)⁺ RNA was electrophoresed through a 1% denaturing agarose gel containing 2.2 mol/L formaldehyde. The RNA was then transferred by capillary blotting to nylon membranes (Hybond N, Amersham) by use of standard procedures and fixed to the membrane by being baked at 80°C for 2 hours. Additional lanes with 25 µg total lung or liver RNA were used as positive controls. Blots were prehybridized at 40°C for at least 3 hours with hybridization solution (50% deionized formamide; 5x SSC [1x SSC=0.15 mol/L sodium chloride, 0.015 mol/L sodium citrate, pH 7.0]; 5x Denhardt's solution [0.1% Ficoll 400, 0.1% polyvinylpyrrolidone, 0.1% bovine serum albumin]; 50 mmol/L Na₃PO₄, pH 6.5; 0.1% SDS; and 250 µg/mL salmon sperm DNA). The hybridizations were carried out in fresh hybridization solution containing 1x10⁶ cpm/mL ³²P-labeled complementary DNA (cDNA) probes overnight at 40°C in a rotating drum. After hybridization, membranes were washed twice in 2x SSC, 0.1% SDS for 20 minutes and then in 0.2x SSC, 0.1% SDS for 30 minutes at 40°C, and they were then exposed to XAR Kodak x-ray film with an image-intensifying screen at -70°C. Exposure times varied from overnight to 10 days. The membranes were rehybridized with a probe encoding the housekeeping gene for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to control for loading errors or transfer variations. The autoradiograms were scanned with a computer-assisted videodensitometer (Bio-Profil, Vilber Lourmat). The relative values of the mRNA levels were corrected for the GAPDH mRNA by dividing the respective densitometric signal densities. The ratio obtained in each sham-operated rat was set at 100%, and the relative levels of Aogen, renin, ACE, and AT₁ receptor mRNA in each 2K1C rat were expressed as percentage compared with the time-matched control.

cDNA Probes
The following cDNA probes were used for the RNA hybridization studies: a 712-bp BamHI fragment of rat Aogen (position 424 to 1136) subcloned into pSPT18 vector plasmid (pRAN2 clone⁸ ); a 1424-bp BamHI-HindIII insert from the rat renin full-length cDNA subcloned in pGem4 vector⁹ ; an EcoRI insert of the mouse ACE cDNA clone pACE.31¹⁰ ; a 714-bp Kpn I–EcoRI insert of rat AT₁ subcloned into pGem5¹¹ ; and a Pst I fragment encoding the rat GAPDH subcloned in pSPT19 vector. The cDNA probes were labeled with [³²P]deoxycytidine by the random priming method with the Megaprime DNA labeling system (Amersham).

Statistical Analysis
The data are expressed as mean±SEM. Significance of differences between 2K1C and sham-operated rats was assessed by the nonparametric Mann-Whitney U test. A value of P<.05 was considered significant. Significance of correlations was assessed by the nonparametric Spearman's rank-order correlation test. Statistics were carried out using CSS Statistica (STATSOFT) software.

	Results

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Systolic blood pressure was not increased during the first 2 days after clipping of the renal artery but was significantly elevated in 2K1C rats at day 4 (Fig 1). This observation was confirmed by intra-arterial blood pressure recordings performed on day 4 (Table 1). Systolic blood pressure measured by tail-cuff plethysmography correlated with systolic (r=.80, P<.0001), diastolic (r=.79, P<.0001), and mean (r=.79, P<.0001) arterial pressures obtained by intra-arterial recordings (Table 1). Blood pressure of 2K1C rats increased further during the 28 days after operation (Fig 1, Table 1). Table 2 shows that hypertension was associated with a significant increase in the relative heart and nonclipped kidney weights. The relative weight of the left clipped kidney remained unchanged until day 14; a slight decrease could be measured at day 28. In 2K1C rats, both PRA (9.18±2.24 ng Ang I · mL^-1 · h^-1 in 2K1C versus 3.71±1.18 ng Ang I · mL^-1 · h^-1 in control rats, P<.05) and Ang II (73±9 fmol/mL in 2K1C versus 54±6 fmol/mL in controls, P<.05) were increased at 4 days as well as at 19 days (PRA, 150.3±30.6 ng Ang I · mL^-1 · h^-1 in 2K1C versus 5.8±1.1 ng Ang I · mL^-1 · h^-1 in controls, P<.0001; Ang II, 132±18 fmol/mL in 2K1C versus 43±3 fmol/mL in controls, P<.0001) after clipping. PRA was correlated with Ang II (r=.75, P<.0001). Mean arterial pressure correlated with PRA (r=.90, P<.0001) and Ang II (r=.67, P<.001).

View larger version (13K): [in this window] [in a new window]   Figure 1. Line graph showing systolic blood pressure measured by tail-cuff plethysmography in renovascular hypertensive (2K1C) and sham-operated rats under light ether anesthesia. The time axis indicates days after clipping of the left renal artery or sham operation. Values are mean±SEM. *P<.05, differences between 2K1C and time-matched sham-operated control rats.

View this table: [in this window] [in a new window]   Table 1. Comparison of Direct and Indirect Blood Pressure Recordings

View this table: [in this window] [in a new window]   Table 2. Body and Organ Weights

The densitometric analyses of changes in cortical gene expression of Aogen, renin, ACE, and AT₁ in the kidneys are shown in Fig 2. Because of the need to pool the samples for mRNA purification, variances cannot be indicated. Renin mRNA exhibited a marked downregulation in the nonclipped kidneys and an upregulation in the clipped kidneys throughout the experiment (Fig 2A). ACE mRNA was unchanged or slightly reduced in the nonclipped kidneys, whereas a marked increase of ACE mRNA in clipped kidneys was measured in the prehypertensive phase (day 1, 158% increase; day 2, 87% increase) and throughout the experiment (Fig 2B). Aogen mRNA tended to be decreased in the nonclipped kidney during the development of hypertension but remained unchanged in the clipped kidney (Fig 2C). AT₁ mRNA was decreased in nonclipped kidneys with the development of hypertension but was unchanged or slightly increased in clipped kidneys during the first 7 days after clipping (Fig 2D). Fig 3 shows the autoradiographs of the specific bands obtained by Northern blot analysis.

View larger version (22K): [in this window] [in a new window]   Figure 2. Line graphs showing changes in the relative levels of renin (A), angiotensin-converting enzyme (ACE) (B), angiotensinogen (C), and angiotensin II type 1 receptor (AT1-R) (D) messenger RNA (mRNA) in the nonclipped () and clipped kidneys () of two-kidney, one clip rats. For each point shown, poly(A)+-purified RNA from five animals of each group was pooled. Autoradiographs from Northern blot analysis (see Fig 3) were quantitated by densitometry. The changes in mRNA levels are expressed as percent change from the respective value in time-matched sham-operated controls. The time axis indicates days after clipping the renal artery. Note that the scale for renin is different from that for the other genes.

View larger version (69K): [in this window] [in a new window]   Figure 3. Autoradiographs of the Northern blot analysis (10 µg poly(A)+-purified mRNA per lane). Top, Clipped left kidneys from two-kidney, one clip (2K1C) rats and left kidneys from sham-operated rats. Bottom, Nonclipped right kidneys from 2K1C rats and right kidneys from sham-operated rats. Each sample was pooled from five rats. Autoradiography times differ between complementary DNA probes, time after clipping, and right or left kidneys but were identical for 2K1C and matched sham-operated rats. AT1-R indicates type 1 angiotensin II receptor; ACE, angiotensin-converting enzyme; and GAPDH, glyceraldehyde-3-phosphate dehydrogenase.

	Discussion

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We investigated the expression of the genes of the RAS in both kidneys during the onset and early phase of 2K1C hypertension in the rat. The most important finding of our study was that ACE gene expression in the clipped kidney was markedly increased as early as 1 day after clipping of the renal artery. These data are consistent with a regulatory role for local ACE in increased intrarenal Ang II formation in the poststenotic kidney.

The relationships between renal renin mRNA, PRA, and hypertension have been extensively studied in 2K1C rats.^{2 3 12} Our data confirm and extend these previous reports. We show that the changes of renal renin mRNA may precede the onset of 2K1C hypertension, as in the aortic coarctation model.¹³ The absence of a difference in blood pressure between 2K1C and sham-operated rats 2 days after clipping in our study is documented only by indirect tail-cuff measurements. However, direct intra-arterial measurements on days 4 and 19 clearly demonstrate the reliability of our indirect readings. Moreover, only mild hypertension was measured intra-arterially 4 days after clipping.

ACE mRNA was markedly increased in the clipped kidney 1 day after clipping and remained increased throughout the 4 weeks. In contrast, ACE gene expression in the nonclipped kidney tended to be decreased. To our knowledge, this is the first report describing upregulation of ACE gene expression in the kidney almost immediately after induction of renal artery stenosis. Reports of ACE activity in clipped kidneys in 2K1C hypertension^{14 15} are consistent with our results: ACE activity was increased in rat kidneys clipped for 7¹⁴ or 14¹⁵ days. However, those rats were already markedly hypertensive at the time of study.^{14 15}

Although the essential role of ACE in the generation of Ang II has been known for many years,¹⁶ the notions that ACE may regulate the activity of the RAS and may be subject to feedback regulation by other RAS components¹⁷ have only recently gained attention. Our data, together with previous reports,^{14 15} suggest a novel role for ACE in mediating increased local Ang II formation in the poststenotic kidney, thus contributing to the development of high blood pressure. We can only speculate on the mechanisms leading to increased renal ACE expression. Our data do not support the notion that systemic Ang II elevates renal ACE,¹⁸ because we did not observe increased ACE expression in the nonclipped kidney but rather a tendency toward decreased ACE mRNA levels. Factors other than systemic Ang II are probably involved in the regulation of renal ACE expression.

We did not investigate whether increased ACE expression is localized to the endothelium or the tubular brush border. Increased ACE activity in tubular brush border membranes could mediate elevated local Ang II production, because high concentrations of angiotensin peptides are generated in the tubular lumen.^{19 20} However, Michel et al¹⁵ have shown that the increase of total cortical ACE activity 14 days after renal artery clipping is much greater than the increase of enzyme activity in brush border membranes, supporting the hypothesis that vascular endothelial ACE expression may be increased. Attempts to assess Ang I conversion during passage through poststenotic kidneys in vivo²¹ have been hampered by the almost complete degradation of Ang II in the renal vascular bed.²¹

Aogen mRNA levels showed no change in the clipped kidney and a tendency toward lower levels in the nonclipped kidney during sustained hypertension. These data are essentially consistent with previous reports of unchanged renal Aogen gene expression in both kidneys of 2K1C rats¹² but contrast with the results of Schunkert et al,²² who described increased renal Aogen expression during Ang II infusion. AT₁ receptor gene expression was differentially regulated in both kidneys. In the nonclipped kidney, AT₁ mRNA was decreased along with the development of high blood pressure and elevated plasma Ang II, as expected from previous reports by others.^{13 23} In the clipped kidney, AT₁ mRNA was clearly not decreased. This lack of downregulation might exaggerate the effects of intrarenal Ang II. We can only speculate on the mechanisms regulating differential expression of AT₁ and Aogen in both kidneys. Obviously, systemic Ang II and hypertension alone^{13 18 22 23} cannot account for the pattern of gene expression. Recently, Gomez²³ hypothesized that AT₁ mRNA may be downregulated by stretch, which may explain our findings, because the low perfusion pressure of the poststenotic kidney (ie, the lower stretch) could counteract the influence of Ang II on AT₁ expression.

In summary, our findings emphasize that gene expression of ACE, Aogen, and AT₁ in the kidneys in renovascular hypertension is regulated by local rather than systemic factors. Differential expression of the ACE gene shows a pattern similar to that of renin expression, suggesting that increased ACE in the poststenotic kidney may enhance intrarenal Ang II formation. At present, it is difficult to assess the roles of individual components of the RAS for the development of high blood pressure, because the inhibition of one component necessarily inhibits the entire system. An ACE gene transfer approach, as recently introduced by Morishita et al,²⁴ may be helpful in addressing this question in future research.

	Acknowledgments

 
This work was supported by grants-in-aid Ge 568/2-2 (H.G.) and Hi 510/5-2 (K.F.H.) from the Deutsche Forschungsgemeinschaft, Bonn–Bad Godesberg, Germany. K.F.H. is a recipient of a research fellowship (Hi 510/5-1) from the Deutsche Forschungsgemeinschaft. We thank R. Ariel Gomez for reading the manuscript and for helpful discussion.

	References

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