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(Hypertension. 2005;45:730.)
© 2005 American Heart Association, Inc.

Original Articles

Fenofibrate Prevents the Development of Angiotensin II–Dependent Hypertension in Mice

Trinity Vera; Montoya Taylor; Quinn Bohman; Averia Flasch; Richard J. Roman; David E. Stec

From the Department of Physiology & Biophysics (T.V., M.T., D.E.S.), Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson; and the Department of Physiology (Q.B., A.F., R.J.R.), Medical College of Wisconsin, Milwaukee.

Correspondence to David E. Stec, PhD, Assistant Professor, Department of Physiology and Biophysics Center for Excellence in Cardiovascular-Renal Research, 2500 North State Street, Jackson, MS 39216-4505. E-mail dstec{at}physiology.umsmed.edu

	Abstract

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Previous studies have indicated that the production of 20-hydroxyecisatatraenoic acid (20-HETE) is similar in the liver of C57/B6 mice and rats, but the renal production of 20-HETE is very low in this strain of mice. The present study examined the effects of induction of the renal production of 20-HETE with fenofibrate (FF) on the development of angiotensin II (Ang II)–dependent hypertension in C57BL/6J mice. The mice were divided into 4 groups and treated with vehicle (control), FF (90 mg/kg per day, IP), Ang II (1000 ng/kg per minute, SC), and Ang II plus FF. Mean arterial blood pressure (MAP) averaged 109±4 and 106±2 mm Hg in control and FF-treated mice (n=7). MAP was significantly increased in the Ang II-treated mice to 144±4 mm Hg (n=7). However, FF treatment prevented the development of Ang II–dependent hypertension, with MAP averaging 115±5 mm Hg in mice treated with both Ang II plus FF (n=7). Renal production of 20-HETE was very low in control (n=7) and Ang II-treated (n=7) mice and was increased by >2-fold in FF-treated (n=7) and Ang II plus FF-treated (n=7) mice. The levels of Cyp4A proteins were markedly increased in the kidneys of mice treated with FF and Ang II plus FF but not in the renal vasculature. These results suggest that upregulation of the production of 20-HETE in renal tubules may contribute to the blood pressure-lowering effects of FF treatment in Ang II–dependent hypertension in C57BL/6J mice.

Key Words: hypertension • angiotensin II • mice • kidney • arachidonic acids

	Introduction

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Cytochrome P450 (CYP)-derived metabolites of arachidonic acid (AA) are important regulators of renal vascular tone and tubular function.¹ Of these metabolites, 20-hydroxyecisatatraenoic acid (20-HETE) has been reported to inhibit sodium transport and promote natriuresis.^2,3 Studies in Dahl salt-sensitive (Dahl S) rats indicate that production of 20-HETE in the outer medulla is reduced and that this defect contributes to the development of salt-sensitive hypertension in this model.^4,5 Induction of the renal expression of Cyp4a enzymes in the kidney using fibrate compounds has been reported to lower blood pressure in spontaneously hypertensive rats (SHR) and stroke-prone SHR and Dahl S rats.^6,7 The reduction of blood pressure with clofibrate in Dahl S rats was also associated with the normalization of the pressure–natruretic response in this model.⁸ In mice, the expression of Cyp4A proteins and renal 20-HETE production is reduced during the development of deoxycorticosterone acetate-salt hypertension.⁹ Induction of the renal production of 20-HETE with bezafibrate lowered the blood pressure and improved renal hemodynamics in this model.¹⁰ These studies suggest that a deficiency in the renal production of 20-HETE may promote the development of hypertension. More recently, we have reported that the renal production of 20-HETE is also very low in the kidney of C57BL/6J mice,¹¹ indicating that they may be a good model to determine the role of CYP metabolites of AA in the regulation of renal function and blood pressure. Thus, the present study examined the effects of induction of the renal production of 20-HETE with FF on the development of Ang II–dependent hypertension in C57BL/6J mice.

	Methods

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Animals
Experiments were performed on 12- to 16-week-old male C57BL/6J mice obtained from Jackson Labs (Bar Harbor, Me). The mice were fed a standard diet containing 0.29% NaCl and were provided water ad libitum. All animal protocols were approved by the Institutional Animal Care and Use Committee at the University of Mississippi Medical Center and performed in accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The mice were randomly divided into 4 treatment groups and were treated with vehicle (corn oil; control), fenofibrate-treated (FF; 90 mg/kg per day, IP), angiotensin II-treated (Ang II; 1000 ng/kg per minute, SC), and Ang II plus FF-treated mice. Fenofibrate treatment was started 2 days before exposure to Ang II. Ang II was delivered using an osmotic minipump that was subcutaneously implanted. Ang II was infused for 12 days.

Blood Pressure
Blood pressure was directly measured via microrenathane catheters implanted into the carotid artery using aseptic surgical technique as previously described.¹² Surgery was performed 5 days after implantation of the minipumps and the mice were allowed 2 days to recover from surgery. Mean arterial blood pressure (MAP) was recorded from conscious, freely moving mice for 3 hours per day, on days 7 to 12 after initiation of infusion of Ang II. Because the level of blood pressure recorded over the 5-day period was relatively stable in all the mice, the data are presented as the average of the individual daily recordings over this time period.

Measurement of AA Metabolism
The CYP-dependent metabolism of AA was determined by incubating microsomes prepared from the whole kidney or the liver (0.5 mg protein), with a saturating concentration of [¹⁴C]AA (1 µCi; 42 µmol/L) in an NADPH-regenerating system as previously described.¹¹ The reactions were terminated by the acidification with formic acid and were then extracted twice with ethyl acetate and dried under N₂ gas. The metabolites were then resuspended in 500 µL of 100% ethanol and separated by high-performance liquid chromatography (HPLC). The metabolites were monitored using a radioactive flow detector as previously described.¹¹ The production of each metabolite was calculated and expressed as picomoles formed per minute per milligram of protein.

Real-Time Polymerase Chain Reaction
RNA was prepared from tissues using a modified guanidine thiocyanate method and then treated with DNase to remove any contaminating DNA. First-strand synthesis was performed with iScript cDNA Synthesis system (BioRad) and 1 µg of total RNA using random hexamer primers. Reactions lacking reverse-transcriptase were used as negative controls. After the reverse-transcription reaction, cDNAs were diluted 1:10 for use in polymerase chain reaction. Real-time polymerase chain reaction was performed using iQ SYBR Green Supermix in a 25-µL reaction volume. Data analysis was performed using Icycler IQ software (BioRad, Hercules, Calif). Expression of each Cyp4A mRNA relative to GAPDH was calculated based on the change in threshold cycle, in which C_T=C_T,target – C_T,GAPDH and normalized between controls and each experimental treatment group and expressed as –(C_T). Using this method, a mRNA that is expressed at a greater level in the experimental as compared with the control will have a negative C_T value and a positive –(C_T) value. The relative fold expression can be calculated as 2^–(CT). Experiments were performed on RNA isolated from 3 individual mice per group.

Immunoblots
Western Blots for Cyp4A proteins were performed on microsomes prepared from whole kidneys, liver, and renal blood vessels. Renal vessels were prepared from the kidneys of control and mice treated with FF for 14 days as previously described.¹¹ Microsomal proteins (10 µg) were separated on 7.5% SDS-polyacrylamide gels and blotted onto nitrocellulose membrane. Membranes were blocked with Odyssey blocking buffer (LI-COR, Lincoln, Neb) for 2 hours at room temperature and were incubated with a goat anti-rat Cyp4A1 polyclonal (Daiichi Pure Chemicals Co, Tokyo, Japan) antibody and a mouse anti-ß-actin antibody overnight at 4°C. The membranes were then incubated with both Alexa 680 goat anti-rabbit IgG (Molecular Probes) and IRDye 800 goat anti-mouse IgG (Rockland, Gilbertsville, Pa) for 1 hour at room temperature and visualized using an Odyssey infrared imager (Li-COR), which allows for the simultaneous detection of 2 proteins. Densitometry analysis was performed using Odyssey software (LI-COR). Levels of Cyp4A proteins were expressed as the ratio of Cyp4A to ß-actin for each sample.

Statistics
Mean values±SE are presented. Significant differences between mean values were determined with the use of an ANOVA, followed by a post hoc test (Dunnet). P<0.05 was considered to be significant.

	Results

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Blood Pressure
MAP over the entire 5-day recording period was not significantly different between control and FF-treated mice. MAP increased significantly by 40 mm Hg in mice infused with Ang II. FF treatment prevented the development of Ang II-dependent hypertension (Figure 1). No significant difference in heart rates was observed between the groups (601±16 versus 616±14 versus 625±13 versus 586±13 beats per minute; control versus FF versus Ang II versus Ang II plus FF), although the heart rate in Ang II plus FF group was slightly lower than that measured in the other groups.

View larger version (17K): [in this window] [in a new window]   Figure 1. Comparison of mean arterial pressure in control, FF-treated, Ang II–treated, and FF plus Ang II–treated mice. Mean arterial pressures were recorded for 3 hours per day on 5 consecutive days in conscious mice 7 days after the start of Ang II administration. *Significant difference from control (P<0.05).

P450 Activity
The renal production of 20-HETE was very low in control kidneys, and Ang II infusion further reduced the renal production of 20-HETE by 25% from control. Renal 20-HETE production was increased significantly in both the FF and FF plus Ang II groups (Figure 2A). Total production of EETs and DiHETEs was reduced by Ang II infusion and increased significantly after FF treatment (Figure 2B).

View larger version (15K): [in this window] [in a new window]   Figure 2. A, Renal 20-HETE and (B) total epoxide production in control, Ang II–treated, FF-treated, and FF plus Ang II–treated mice. 20-HETE and total epoxide production was determined by incubating purified kidney microsomes with saturating concentrations of [14C] AA. *Significant difference from (A) control and (B) Ang II–reated (P<0.05).

The production of 20-HETE in microsomes prepared from the liver was 5-fold higher that that seen in the kidney. No significant difference in 20-HETE production was observed between control and Ang II mice. FF treatment significantly increased hepatic 20-HETE production by 5-fold in both FF-treated and FF plus Ang II–treated mice (Figure 3A). No differences in the production of total epoxide metabolites (EETs plus DiHETEs) were observed between the groups (Figure 3B).

View larger version (16K): [in this window] [in a new window]   Figure 3. A, Hepatic 20-HETE and (B) total epoxide production in control, Ang II–treated, FF-treated, and FF plus Ang II–treated mice. Hepatic 20-HETE and total epoxide production was determined by incubating purified liver microsomes with saturating concentrations of [14C] AA. *Significant difference from control (P<0.05).

Cyp4A Expression
The levels of the Cyp4a10, 4a12, and 4a14 in the kidney were all significantly increased by FF treatment, translating into a 90-, 40-, and 2300-fold increase in the levels of each of these messages as compared with control kidneys (Figure 4A). Treatment with both FF and Ang-II also increased the levels of the Cyp4a10 and Cyp4a14 mRNA in the kidney but the magnitude of the increase was less than that observed in mice treated with FF alone. The levels of the Cyp4a12 mRNA in the kidney did not increase in mice treated with FF and Ang II. Interestingly, Ang II treatment alone was associated with a decreased in the levels of the Cyp4a10 (20%) and 4a12 (50%) isoforms as determined by real-time reverse-transcriptase polymerase chain reaction. However, Ang II treatment was able to increase the levels of the Cyp4a14 isoform by 9-fold as compared with control kidneys (Figure 4A). Similar effects on the levels of the Cyp4a10, 4a12, and 4a14 isoforms by each treatment were also observed in the liver (Figure 4B).

View larger version (13K): [in this window] [in a new window]   Figure 4. Relative expression of the Cyp4A10, 4A12, and 4A12 mRNAs in the kidney and liver of FF-treated, FF plus Ang II-treated, and Ang II-treated mice as determined by real-time polymerase chain reaction (PCR). Threshold cycles of the 3 Cyp4A isoforms were internally normalized to GAPDH housekeeping gene (CT) and compared with the levels in control kidneys and livers (CT). Data are presented as the average of the –CT in 3 mice per group.

We also determined the effects of each treatment on the level of Cyp4a proteins in the kidney and liver. FF and FF plus Ang II treatment produced a dramatic increase in the levels of immunoreactive Cyp4a protein in the kidney and liver (Figures 5 and 6). Ang II treatment alone lead to significant reductions in the Cyp4a protein levels in the kidney and the liver, similar to the effects that it had on the levels of Cyp4a10 and 4a12 mRNA in these tissues. Finally, we examined the effect of FF treatment on the levels of Cyp4a proteins in renal microvessels between 40 and 150 µmol/L. No differences in the levels of immunoreactive Cyp4a proteins were detected between the groups (Figure 7).

View larger version (54K): [in this window] [in a new window]   Figure 5. Comparison of the levels of Cyp4a protein in the kidney of control, FF-treated, Ang II plus FF-treated, and Ang II–treated mice. Top, Representative blot loaded with 10 µg microsomal protein from the kidneys of control (lane 1), FF-treated (lanes 2 to 3), FF plus Ang II–treated (lanes 4 to 5), and Ang II–treated (lanes 6 to 7) mice. Bottom, Densitometric analysis of the relative levels of Cyp4A proteins in the kidney of 6 mice per group. *Significant difference from control (P<0.05).

View larger version (55K): [in this window] [in a new window]   Figure 6. Comparison of the levels of Cyp4a protein in the liver of control, FF-treated, Ang II plus FF-treated, and Ang II–treated mice. Top, Representative blot loaded with 10 µg microsomal protein from the liver of control (lanes 1 to 2), FF-treated (lanes 3 to 4), FF plus Ang II–treated (lanes 5 to 6), and Ang II–treated (lanes, 7 to 8) mice. Bottom, Densitometric analysis of the relative levels of Cyp4A proteins in the liver of 6 mice per group. *Significant difference from control (P<0.05).

View larger version (40K): [in this window] [in a new window]   Figure 7. Comparison of the levels of Cyp4a proteins in renal vessels of control and FF-treated mice. Top, Representative blot loaded with 10 µg microsomal protein from control (lanes 1 to 3) and FF-treated (lanes 4 to 6) mice. Bottom, Densitometric analysis of the relative levels of Cyp4A proteins in the renal vessels of 3 mice per group.

	Discussion

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The role of renal tubular versus vascular-derived 20-HETE in the regulation of blood pressure is a highly controversial area of research. Early studies in the SHR suggested that an increase in vascular-derived 20-HETE acts to enhance preglomerular vascular tone, which leads to resetting of the pressure–natriuretic response and the development of hypertension.^13,14 This hypothesis is consistent with the observations that acute treatment of SHR with ABT, an inhibitor of 20-HETE production, or antisense oligonucleotides directed against the Cyp4a1 isoform is able to decrease vascular reactivity and lower blood pressure.^15,16 However, the results of other studies indicating that the induction of the renal production of 20-HETE with fibrates reduces blood pressure in the SHR have suggested an opposing role for tubular derived 20-HETE in the regulation of blood pressure in this model.⁷ It has been difficult to dissect out the role of renal vascular versus renal tubular-derived 20-HETE in the regulation of blood pressure. Recently, we have reported that the C57BL/6J mouse exhibits a selective deficiency in the renal production of 20-HETE, indicating that it might be a useful model for studying the role of CYP eicosanoids in the regulation of renal function and blood pressure.¹¹ We hypothesized that decreased production of 20-HETE in the kidney of C57BL/6J mice (indicting low tubular levels of 20-HETE) might contribute to the development of Ang II-dependent hypertension in this strain. The present study examined the effects of induction of renal 20-HETE production with FF on the development of Ang II–dependent hypertension in this strain.

The results of the present study are consistent with previous reports of the antihypertensive actions of Cyp4a induction in the kidney^6,7,10 and underscore the important role of tubular derived 20-HETE in the pressure–natriuretic response. Cyp4a protein levels were not different after FF treatment in vessels isolated from the kidney, suggesting that FF is only able to increase 20-HETE production in the renal tubules. The lack of effect of FF on Cyp4a protein levels in the vasculature of the kidney may be caused by lack of peroxisome-activated receptor- receptors on renal vessels as previously reported in the rat.¹⁷ Studies in the Dahl S rat have clearly indicated a role for altered outer medullary 20-HETE production in the development of salt-sensitive hypertension in this model.^4,5 Similar observations between urinary levels of 20-HETE and sodium excretion have recently been reported in salt-sensitive versus salt-resistant patients.^18,19 These studies suggest that alterations in renal 20-HETE production may be involved in the development of salt-sensitive hypertension; nonetheless, it should be noted that at this point in time, specific deficits in tubular 20-HETE production have not been identified in salt-sensitive hypertensive populations.

We cannot rule out the possible role of increased renal production of EETs in mediating the antihypertensive actions of FF in the present study. As seen with 20-HETE, FF treatment also leads to a significant increase in the renal formation of epoxygenase metabolites in Ang II–treated mice. Recent studies have reported decreased EET production in Ang II–dependent hypertension and that increasing the levels of EETs can augment the increase in blood pressure and renal damage in this model.^20–22 The potential role of EETs in the blood pressure-lowering response of FF in Ang II–dependent hypertension could be addressed in future studies by co-administration of a specific Cyp4A inhibitor such as HET0016;²³ however, these studies are limited by the ability to effectively deliver these inhibitors for chronic periods of time in vivo. The induction of EETs in the kidney of FF-treated mice was an unexpected finding given that treatment of rats with fibrates leads to induction of renal 20-HETE production and diminished formation of EETs and other HETEs.^7,8 This differential response could be caused by differences in the CYP proteins induced by fibrates between the species, or by differences in the substrate specificity of the isoforms induced by fibrates in the kidney versus the liver in C57BL/6J mice.

Direct activation of peroxisome-activated receptor- by FF can also have potential blood pressure-lowering effects during Ang II hypertension. Previous studies have indicated that activation of peroxisome-activated receptor- can reduce oxidative stress and inflammation in Ang II hypertension by effecting the function of NADPH oxidase and the transcription of several proinflammatory genes.^24,25 Decreases in these parameters may be helpful to improve endothelial dysfunction observed in Ang II hypertension and contribute to the blood pressure-lowering effects of FF treatment.

One interesting finding is that the development of hypertension in Ang II-treated C57BL/6J mice was associated with a decline in the renal production of 20-HETE and the levels of Cyp4a mRNA and protein in this strain. However, previous studies in the rat have suggested that Ang II upregulates the production of 20-HETE production in renal microvessels,²⁶ tubules,²⁷ and the kidney.²⁸ In the mouse, Ang II specifically reduced the expression of the Cyp4a10 and 4a12 mRNAs, whereas the levels of the 4a14 mRNA increased. The Cyp4a10 and 4a12 isoforms are believed to be the major isoforms responsible for the production of 20-HETE in the mouse kidney.²⁹ This downregulation of the expression of the isoforms likely accounts for the diminished renal production of 20-HETE observed in the current study. There are several possible explanations for the differences in the effects of Ang II administration on Cyp4a levels and 20-HETE production between mice and rats. The observed disparity could be caused by differences in the signal transduction mechanism by which Ang II regulates Cyp4a genes in mice and rats, or there may be differences in the substrate specificity of the CYP isoforms that metabolize AA in the kidney between the 2 species. The latter possibility is further warranted by the markedly reduced 20-HETE production in the kidney versus the liver of C57BL/6J mice observed in the present study, as well as a in previous study using this strain.¹¹ Basal levels of 20-HETE production in the kidney are 5-times less than those observed in the liver, even though the levels of Cyp4a proteins are equivalent in the 2 tissues (unpublished observation, D.E.S.). The reason for the diminished 20-HETE production in the kidney of C57BL/6J mice is currently unknown, but it may be specific for this strain because the levels of 20-HETE production in the kidney of mice on a mixed 129 genetic background were found to be higher; however, the levels of 20-HETE produced in the liver of these mice were not reported.²⁹

Perspectives
The results of the current study provide further support for increased renal P450 eicosanoid production to lower blood pressure in Ang II–dependent hypertension. However, future studies in which the levels of 20-HETE or EETs can be individually altered in specific nephron segments will be required to determine which P450 metabolite produced in which specific tubular site provides the most antihypertensive benefit in several model of hypertension. With this knowledge, strategies in which these metabolites are selectively elevated in specific nephron segments could be developed as novel antihypertensive therapies for humans.

	Acknowledgments

 
This work was supported by an American Heart–Heartland Affiliate Beginning grant-in-aid and National Scientist Development grant (to D.S.), as well as grants from the National Heart, Lung, and Blood Institute PO1HL-5197 and HL36279.

	Footnotes

 
This paper was sent to Ernesto Schiffrin, associate editor, for review by expert referees, editorial decision, and final disposition.

Received October 7, 2004; first decision November 1, 2004; accepted December 3, 2004.

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