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(Hypertension. 1996;27:399-403.)
© 1996 American Heart Association, Inc.

Articles

Renin Is Expressed in Rat Macrophage/Monocyte Cells

Naoharu Iwai; Tadashi Inagami; Nobuyuki Ohmichi; Masahiko Kinoshita

From the First Department of Internal Medicine, Shiga University of Medical Sciences, Ohtsu-city, Shiga, Japan, and the Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tenn (T.I.).

Correspondence to Naoharu Iwai, MD, First Department of Internal Medicine, Shiga University of Medical Sciences, Tsukinowa Seta, Ohtsu-city, Shiga-ken, Japan.

	Abstract

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Abstract The cardiac renin-angiotensin system has been suggested to be involved in various pathological conditions, including hypertrophy and remodeling. However, direct evidence that the renin synthesized in situ is really involved in the putative angiotensin II generation is still lacking because of the relatively low abundance of renin mRNA in cardiac tissues. We evaluated renin mRNA expression levels in the ventricles under various pathological conditions and found that renin gene expression was markedly increased in the ventricles of isoproterenol-treated rats. Renin mRNA expression levels in the ventricles of rats that had been injected with isoproterenol (150 mg/kg SC) were transiently and markedly increased to 6-, 90-, and 4-fold compared with control expression levels at 24, 72, and 120 hours, respectively, after isoproterenol administration. Immunohistochemical analysis revealed that some of the OX-42–positive macrophage/monocyte cells had a reninlike immunoreactivity. An in vitro experiment indicated that rat peritoneal macrophage/monocyte cells expressed renin mRNA in abundance. The present study confirmed that a subpopulation of macrophage/monocyte cells could express renin. Macrophage/monocyte cells may be a source of tissue renin in some pathological conditions.

Key Words: macrophage • renin • infarction • isoproterenol

	Introduction

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The RAS plays important roles not only in the regulation of blood pressure but also in several cardiovascular pathological conditions, including cardiac and vascular hypertrophy and remodeling.^{1 2} Increasing evidence suggests that angiotensins are produced not only in the circulation but also in local peripheral tissues, including the kidney, adrenal, brain, peripheral vasculature, and cardiac tissues.^{3 4 5 6}

It has been suggested that a cardiac Ang II–generating system may be involved in cardiac hypertrophy and cardiac remodeling after myocardial infarction. Indeed, induction of gene expression for angiotensin-converting enzyme,^{7 8} angiotensinogen,⁹ and angiotensin type I receptor^{10 11} has been reported in pressure-overloaded cardiac hypertrophy and myocardial infarction. However, direct evidence for Ang I generation in the heart by the renin synthesized in situ is lacking. Renin mRNA levels in cardiac tissues are reportedly very low and can be detected only by PCR.^{12 13} Therefore, it is now generally believed that at least in the healthy heart, renin in cardiac tissues originates from the kidney, and angiotensin production in cardiac tissues depends on plasma-derived renin.^{6 14}

To our knowledge, there has been no extensive analysis of renin gene expression in cardiac tissues under various pathological conditions. The purpose of the present study was to assess renin expression in the ventricle of the heart under various pathological conditions and to investigate the possibility that renin synthesized in situ might be involved in Ang II generation in the heart. Our results indicate that renin can be expressed in macrophage/monocyte cells infiltrating necrotic myocardium.

	Methods

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Animals
Male Wistar rats (Charles River Laboratories) weighing 250 to 300 g at the time of isoproterenol administration were kept at a controlled room temperature with light from 6 AM to 6 PM and were fed regular pelleted rat chow and tap water ad libitum.

Renin mRNA expression levels in the left ventricle were assessed in rats under various pathological conditions, including bilateral nephrectomy, which was the most potent upregulator of renin gene expression in the adrenal gland; administration of angiotensin-converting enzyme inhibitors; hypertension with marked cardiac hypertrophy induced by coarctation of the aorta; and isoproterenol-induced myocardial necrosis. However, only isoproterenol-induced myocardial necrosis upregulated the expression level of the renin gene in the left ventricle. Therefore, only the findings with isoproterenol-induced myocardial necrosis are described here.

Isoproterenol dissolved in 150 mmol/L NaCl was administered at a dose of 150 mg/kg SC. Our preliminary experiments showed that this dose was sufficient to produce extensive myocardial necrosis. Nevertheless, fewer than 10% of the rats died during the following 7 days.

RNA Isolation and Analysis
RNA was isolated as previously reported.¹⁵ The quality of RNA analyzed in the present study was confirmed by ethidium bromide staining. The expression level of renin mRNA was determined by the RT-PCR method because of relatively low expression levels of this mRNA in the ventricle of the heart, as previously reported.¹³ The validity of this method has been previously examined in detail.¹³

Briefly, 4 µg total RNA samples mixed with a known amount of the deletion-mutated renin cRNA (9.6x10⁴ or 9.6x10⁵ molecules; 2.4x10⁴ or 2.4x10⁵ molecules per microgram RNA) was reverse transcribed with random primers. The resulting cDNA mixture was purified by phenol/chloroform extraction and two rounds of ethanol precipitation with ammonium acetate and was dissolved in 40 µL water. Five microliters of the cDNA mixture was amplified in a total 25 µL of reaction mixture containing 50 mmol/L KCl, 10 mmol/L Tris-HCl (pH 8.3), 2.0 mmol/L MgCl₂, 0.01% (wt/vol) gelatin, 0.2 mmol/L dNTP, 50 nmol/L [-³²P]dCTP (3000 Ci/mmol), 25 pmol of primers 1 and 2, and 0.5 U Taq DNA polymerase (Toyobo). The PCR amplification profile included an initial denaturing step of 94°C for 1 minute and 35 cycles at 94°C for 1 minute, 58°C for 1 minute, and 74°C for 2 minutes. The PCR products were electrophoresed on a 1.7% agarose gel for visual inspection and on a 5% polyacrylamide gel for precise quantification, as previously reported.¹³ The sense primer 1 (747-776) was 5'-CTGGGAGGCAGTGACCCTCAACATTACCAG-3', and the antisense primer 2 (1118-1089) was 5'-GAGAGCCAGTATGCACAGGTCATCGTTCCT-3'.

In the present study, the renin mRNA expression levels in samples were calculated as follows: Expression Level (Molecules/µg)=Amount of Deletion-Mutated cRNA for Renin (Molecules/µg)x(Intensity of 327-bp Fragment/Intensity of 263-bp Fragment)x0.625, where 0.625 is the ratio of the dCTP content of the 263-bp fragment to that of the 372-bp fragment. The relative efficiency of RT of the renin mRNA and deletion-mutated renin cRNA for renin is considered to be 1.0 in the present study (Fig 3, top).

View larger version (38K): [in this window] [in a new window]   Figure 3. Top, Validity of RT-PCR assessment of renin mRNA. Synthetic renin cRNA (2.4x104 molecules in 1 µg dog ventricular total RNA) mixed with various amounts of deletion-mutated renin cRNA was reverse transcribed; the resulting cDNA mixture was amplified. The amount of deletion-mutated renin cRNA was 0 (lane 1), 1.2x104 (lane 2), 2.4x104 (lane 3), 4.8x104 (lane 4), 9.6x104 (lane 5), 19.2x104 (lane 6), and 38.4x104 (lane 7) molecules. The ratio of signal intensity in lane 3 was 1.6, which agreed well with the theoretical value of 1.59 (bottom).

Wistar rats were intraperitoneally administered thioglycolate medium (3%) and 2 days later peritoneal lavage was collected. Cells were resuspended in RPMI 1640 containing 10% fetal bovine serum, and cells that adhered to the plastic dish after 2 hours of incubation were used as rat macrophage/monocyte cells.

Immunohistochemistry
Rats were deeply anesthetized with sodium pentobarbital (70 mg/kg). They were perfused via the left ventricle, initially with ice-cold PBS (150 mmol/L NaCl in 10 mmol Na₂HPO₄/NaH₂PO₄, pH 7.4) and subsequently with a fixative containing 4% paraformaldehyde in 0.1 mol/L phosphate buffer (0.1 mol/L Na₂HPO₄/NaH₂PO₄, pH 7.4). The heart was quickly removed from the chest cavity and sliced into 5- to 6-mm coronal blocks. The blocks were immersed for 2 days in a postfixative containing 4% paraformaldehyde in phosphate buffer at 4°C. The blocks were then placed for 2 days in phosphate buffer containing 15% sucrose. Each block was frozen and cut into 20-µm-thick sections in a cryostat. The sections were rinsed for at least 2 days with several changes of PBST at 4°C before immunohistochemical staining.

Free-floating sections, which were pretreated with 0.5% H₂O₂ in PBST to destroy intrinsic peroxidase activity, were incubated for 2 days at 4°C with goat anti-rat renin antiserum (diluted 1:50 000) or rabbit anti-rat renin antiserum (diluted 1:60 000) for 1 hour at room temperature with biotinylated anti-goat IgG (diluted 1:1000) or anti-rabbit IgG (diluted 1:1000) and for 1 hour at room temperature with an avidin/biotin/peroxidase complex (diluted 1:4000, ABC Elite, Vector). All sera were diluted with PBST, and sections were always rinsed in PBST after each step. Peroxidase activity was revealed by 0.02% 3,3'-diaminobenzidine (Wakenyaku) in 50 mmol/L Tris-HCl (pH 7.6), 0.005% H₂O₂, and 0.3% nickel ammonium sulfate. Control experiments included the substitution of primary antiserum with preimmune serum or preabsorbed serum that showed no specific staining. The preparation of the goat and rabbit antisera to rat renin was performed according to the method previously reported.¹⁶ Its specificity was ascertained by the lack of a cross-reaction with human renin and rat cathepsin D at dilutions greater than 1:500. Used at a dilution of 1:80 000 in the immunohistochemical staining of rat kidney by the method described above, juxtaglomerular cells were stained exclusively.¹⁶

Sections were double immunostained for renin and MRC OX-42 (anti-CD11b/CD11c)^{17 18} for characterization of the cells that expressed renin. Briefly, sections were first incubated for 1 day with mouse monoclonal antibody MRC OX-42 (diluted 1:5000) at 4°C for 1 hour at room temperature with biotinylated anti-mouse IgG (diluted 1:1000) and for 1 hour at room temperature with avidin/biotin/peroxidase complex (diluted 1:4000). After completion of the first 3,3'-diaminobenzidine/nickel reaction for MRC OX-42, which gave a blue-purple reaction product, sections were incubated for a second cycle with the rat renin antiserum as described above. Antibody binding was detected as in the first step cycle, except that avidin/biotin/peroxidase complex was replaced with avidin/biotin/alkaliphosphatase. Alkaliphosphatase activity was revealed by a commercial kit (Vector Red, Vector).

Statistical Analysis
Data are expressed as mean±SD. Statistical analyses were performed with one-way ANOVA. Because Bartlett's test for the homogeneity of variances suggested that within-group variance is not homogenous among the groups, a logarithmic transformation was necessary to allow the use of ANOVA.

	Results

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Subcutaneous administration of isoproterenol to Wistar rats induced diffuse myocardial necrosis in a dose-dependent manner. Our preliminary experiments showed that a dose of 150 mg/kg was sufficient to produce extensive myocardial necrosis (Fig 1A). Moreover, fewer than 10% of the rats died during the following 7 days.

View larger version (102K): [in this window] [in a new window]   Figure 1. Macrophages/monocytes express a reninlike immunoreactivity. A, Subcutaneous administration of isoproterenol induced diffuse myocardial necrosis (original magnification x10). Azan staining of the left ventricle of a rat killed 72 hours after isoproterenol administration. Necrotic tissues are being replaced by fibroblastic tissues. B and C, Reninlike immunoreactivity in necrotic/fibroblastic tissues (original magnifications x10 and x200, respectively). Immunohistochemical analysis indicated that reninlike immunoreactivity could be detected in round and spindlelike cells in the necrotic/fibroblastic tissues. D, Reninlike immunoreactivity in OX-42–positive cells (original magnification x400). Not all of the OX-42–positive macrophage/monocyte cells (blue) showed reninlike immunoreactivity (red). Goat antiserum to rat renin (1:50 000) was used in the experiments shown. Rabbit antiserum to rat renin gave similar results (not shown).

Renin mRNA expression levels in isoproterenol-treated left ventricles were markedly upregulated, as shown in Fig 2 (top). Sixfold and 90-fold increases in expression level were observed at 24 and 72 hours, respectively, after isoproterenol administration. This prominent upregulation was transient, and renin mRNA expression levels in isoproterenol-treated left ventricles at 120 hours after administration were only about four times higher than those in untreated control rats (Fig 2, bottom). Fig 3 (top) shows the validity of the quantitation of renin mRNA by our method. The ratio of the synthetic renin and synthetic deletion-mutated renin RNA is linearly related to the ratio of the signal intensities of each PCR product. Moreover, the efficiencies of RT of the synthetic renin and synthetic deletion-mutated renin RNA are almost the same because 1.6 is the ratio of the dCTP content of each PCR product.

View larger version (56K): [in this window] [in a new window]   Figure 2. Renin mRNA expression levels in ventricles. Top, Four micrograms total RNA mixed with 9.6x104 molecules of deletion-mutated renin cRNA (2.4x104 molecules per 1 µg RNA) was reverse transcribed; the resulting cDNA mixture was amplified by PCR. In the upper blot, lanes 1 and 6, RNAs obtained from control rats; lanes 2 through 5, from rats killed 24 hours after isoproterenol administration; lanes 7 through 11, from rats killed 72 hours after isoproterenol administration. RNA corresponding to lane 7 was directly amplified without RT (lane 12). No significant PCR product was visible, which excludes the possibility of contamination by renin cDNA. Since renin mRNA expression levels in ventricles of isoproterenol-treated rats were high, the levels were reassessed with 9.6x105 molecules of renin cRNA per 4 µg total RNA as a competitor (2.4x105 molecules per microgram RNA) (middle blot, samples 6 through 9). Total RNA quality was verified by ethidium bromide staining (lower blot). Bottom, Bar graph summarizes renin mRNA expression levels in left ventricles; cont indicates control.

To clarify which cells express renin in this diffuse myocardial necrosis model, we performed immunohistochemical analysis using a specific antiserum to rat renin. As shown in Fig 1B, a reninlike immunoreactivity was detected in round and spindlelike cells in the fibrous tissues of necrotic myocardium. Reninlike immunoreactivity was intensely stained in a granular manner in the cytoplasm of these cells. This immunoreactivity and the number of cells expressing this immunoreactivity decreased at 120 hours after isoproterenol administration (data not shown), which is in good agreement with the time course of the renin mRNA expression. To identify the cellular origin of these reninlike immunoreactivity–positive cells, we tested distributions of various marker proteins, including vimentin, smooth muscle cell–specific actin, endothelial nitric oxide synthase, inducible nitric oxide synthase, T cell–specific antigen, and the macrophage/monocyte marker OX-42. The distribution pattern of the OX-42–positive cells was similar to that of the reninlike immunoreactivity–positive cells. Indeed, double staining with the renin antiserum and OX-42 revealed that the cells with the reninlike immunoreactivity reacted positively with OX-42. However, not all of the OX-42–positive cells expressed the reninlike immunoreactivity (Fig 1D).

The expression of renin mRNA was confirmed by RT-PCR in the peritoneal macrophage/monocyte cells, and its expression level was almost comparable to that in the kidney (Fig 4).

View larger version (56K): [in this window] [in a new window]   Figure 4. Top, Blot shows renin mRNA expression in macrophage/monocyte cells, which was confirmed in vitro. Four micrograms total RNA isolated from kidney (lanes 1 through 4) or peritoneal macrophage/monocyte cells (Macro, lanes 5 through 8) mixed with 2.4x107 molecules of deletion-mutated renin cRNA for renin was reverse transcribed and amplified by PCR. Bottom, Bar graph summarizes the results.

	Discussion

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Presence of Renin in Macrophages/Monocytes
The present study demonstrated that a subpopulation of macrophage/monocyte cells infiltrating the fibrotic tissues of necrotic myocardium possessed a reninlike immunoreactivity, and renin mRNA expression levels in the ventricles closely paralleled the number of macrophage/monocyte cells expressing this reninlike immunoreactivity. These results strongly suggest that a subpopulation of macrophage/monocyte cells expresses renin. The in vitro experiment, in which peritoneal macrophage/monocyte cells expressed abundant renin mRNA, also strongly supports the idea that a subpopulation of macrophage/monocyte cells infiltrating necrotic myocardium expresses renin. However, we cannot exclude the possibility that renin may also be synthesized in myocytes or other cells and then taken up and concentrated in this subpopulation of macrophages/monocytes. Additional study will be necessary to resolve this problem.

Our present observations agree with the previous findings that human mononuclear leukocytes contain a substantial amount of Ang I and II¹⁹ and that renin activity and immunoreactivity have been detected in resident alveolar macrophages/monocytes.²⁰

Clinical Implications
Ang II is not only a vasoactive polypeptide but also a growth-promoting factor. Ang II has mitogenetic effects on cardiac fibroblasts and stimulates extracellular matrix formation.²¹ The finding that angiotensin-converting enzyme inhibitors attenuate ventricular remodeling after myocardial infarction^{22 23} suggests that the tissue RAS plays an important role in ventricular remodeling. A problem regarding the tissue RAS is whether renin is actually synthesized in cardiovascular tissues.^{24 25} Renin mRNA expression levels in cardiovascular tissues are usually very low and not upregulated by blockade of the RAS.^{5 12 13} Therefore, it has recently been thought that the renin secreted from the kidney is absorbed by peripheral tissues, and this absorbed renin may generate Ang II in situ.^{5 6 14} Our present findings indicate that the source of the renin in cardiovascular tissues under certain conditions may be a subpopulation of macrophage/monocyte cells.

Demonstration of renin expression in macrophage/monocyte cells suggests that the tissue RAS may be involved in an inflammatory process. Macrophage/monocyte cells infiltrating other types of tissue injury such as cerebral infarction caused by transient ischemia and myocardial infarction induced by coronary ligation have indeed expressed renin immunoreactivity, accompanied by an induction of renin mRNA (unpublished observation, 1995). Therefore, the induction of renin in macrophage/monocyte cells may not be peculiar to isoproterenol-induced myocardial infarction and may be a more generalized phenomenon of an inflammatory process. Interestingly, macrophage/monocyte cells are known to express other components of the RAS, including angiotensin-converting enzyme and angiotensin receptors. A possible relationship between the tissue RAS and an inflammatory process has been previously suggested from the fact that angiotensin-converting enzyme inhibitors can suppress granulomatous inflammation.²⁶

The participation of monocytes in hypertension-induced renal injury²⁷ and cardiac fibrosis²⁸ has been recently reported. Therefore, the presence of renin in a subpopulation of macrophage/monocyte cells may be a clue to understanding the mechanism of the efficacy of RAS blockade in preventing hypertension-induced end-organ damage.

In conclusion, renin expression was confirmed in a subpopulation of macrophage/monocyte cells infiltrating the fibrotic tissues of the necrotic myocardium. This finding may lead to a better understanding of the tissue RAS.

	Selected Abbreviations and Acronyms

 

Ang I, II = angiotensin I, II PBS = phosphate-buffered saline PBST = phosphate-buffered saline with 0.3% Triton X-100 PCR = polymerase chain reaction RAS = renin-angiotensin system RT = reverse transcription

	Acknowledgments

 
This study was partly supported by a grant-in-aid of the Japanese Ministry of Education, Science, and Culture. We are indebted to Dr Ikuo Tooyama for histological study.

Received October 19, 1995; first decision November 21, 1995; accepted November 21, 1995.

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