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BASIC SCIENCE |
*Vascular Biology Center, Department of Physiology, Department of Pharmacology, Department of Surgery, Medical College of Georgia, Augusta; ||Department of Entomology, and Cancer Center, University of California at Davis; and ¶First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Correspondence to: Dr. John D. Imig, Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912-2500. Phone: 706-721-1901; Fax: 706-721-9799; E-mail: jdimig{at}mail.mcg.edu
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Abstract |
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Introduction |
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Others and we have found that decreased renal epoxygenase levels are associated with the development of hypertension (1,5,12,13). One approach to increase EET levels chronically is to inhibit the soluble epoxide hydrolase (SEH) enzyme that metabolizes EET to their corresponding DHET. Fortunately, this enzyme represents a single known and highly conserved gene product with over 90% homology between humans, rats, and mice and can be selectively inhibited by a variety of urea, carbamate, and amide derivatives in vivo and in vitro (14–17). On the basis of the anti-inflammatory and antihypertensive properties of EET, we hypothesized that SEH inhibition offers a novel target for the treatment of end organ damage associated with renal and cardiovascular diseases.
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Materials and Methods |
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Measurement of BP
Telemetry transmitters (Data Sciences, St. Paul, MN) were implanted and data collected as described previously (18). Minute-to-minute 24-h measurement of mean arterial pressure as well as the heart rate was obtained. The Biotelemetry Core at the Medical College of Georgia provided assistance with these studies.
Measurement of Oxylipids
The urinary levels of arachidonic and linoleic acid metabolites were measured as described previously (19). Animals were housed in metabolic cages that separated urine from food and feces. Urine was collected in a tube containing 5 mg of triphenylphosphine and cooled with dry ice. Blood was collected into tubes containing heparin and centrifuged to obtain plasma. Samples were stored at –80°C until assayed. Sample aliquots (urine = 4 ml; plasma = 250 µl) were removed from thawed samples. These aliquots were then spiked with analytical surrogates. Urine samples were extracted twice with 2 ml ethyl acetate, and plasma samples were extracted twice with 1 ml ethyl acetate. The combined organic extracts were dried under nitrogen and dissolved in 100 µl of methanol and spiked with internal standards. A 10-µl aliquot of the methanolic extract was then separated by reverse phase HPLC and analyzed by negative-mode electrospray ionization and tandem mass spectroscopy as described previously (19). EET and DHET arachidonic acid metabolites and epoxyoctadecanoic acid (EPOME) and dihydroxyoctadecanoic acid (DHOME) linoleic acid metabolites were assessed.
Assessment of CDU Levels
Urine and plasma samples were collected after the 10-d treatment period. CDU and CDU metabolites were measured as described previously (20). In the case of urine samples, a 500-µl aliquot was spiked with 50 µl ([Final] = 500 ng/ml) of 1-cyclohexyl-3-tetradecylurea as an internal standard. For plasma samples, a 100-µl aliquot was diluted with 200 µl of distilled water and mixed by vortex before internal standard addition. Samples were then mixed, followed by extraction with 500 µl of ethyl acetate. The samples were centrifuged at 6000 rpm for 5 min, and the ethyl acetate was collected. The organic extraction was repeated and the extracts were combined, evaporated to dryness under dry N2 gas, reconstituted in 50 µl of MeOH, and a 5-µl aliquot was analyzed. Mass spectrometry analysis was performed with positive mode electrospray ionization on a Micromass Ultima triple quadrupole mass spectrometer with multireaction monitoring (20).
Isolation of Renal Microvessels
Renal microvessels were isolated according to a method described previously (6). Briefly, the kidneys were infused with a physiologic salt solution containing 1% Evans blue, and the renal microvessels were separated from the rest of the cortex with the aid of sequential sieving, a digestion period and collection under a stereomicroscope. Renal microvessels were collected, quickly frozen in liquid N2, and kept at –80°C in a freezer until assayed for protein levels.
Western Blot Analysis
Renal microvessels and kidney cortical samples were harvested and homogenized for Western blot analysis as described previously (12). Samples were separated by electrophoresis on a 10% stacking Tris-glycine gel, and proteins were transferred electrophoretically to a polyvinylidene fluoride membrane. The primary antibodies used were rabbit anti-mouse SEH antibody (Dr. Hammock) and rabbit anti-rat microsomal epoxide hydrolase (MEH) antibody (Drs. Oesch and Arand, University of Mainz). The blots were then washed and incubated with the goat anti-rabbit secondary antibody conjugated to horseradish peroxidase. Detection was accomplished with enhanced chemiluminescence Western blot test (ECL). Band intensity was measured densitometrically and the values were factored for 
-actin.
Renal Microvascular Responses
In vitro perfused juxtamedullary nephron preparation was used to assess renal microvascular reactivity as described previously (6). The isolated kidney was perfused with a reconstituted red blood cell containing solution and renal artery perfusion pressure was set to 100 mmHg. After a 20-min equilibration period, an afferent arteriole was chosen for study and baseline diameter was measured. After control diameter measurements, angiotensin (0.1 to 10 nM) was delivered by superfusion and a concentration response curve was obtained. Each vessel then underwent a 5-min recovery period before being exposed to 1 µM CDU for 10 min. Angiotensin containing solution was reintroduced after SEH inhibition and the afferent arteriolar response was reassessed.
Evaluation of Renal Vascular and Glomerular Injury
At the end of the 10-d CDU treatment period, kidneys were immediately fixed in 10% buffered formalin solution and embedded in paraffin for light microscopic evaluation. Sections were cut at a thickness of 2 to 3 µm and stained with hematoxylin-eosin, periodic acid-Schiff reagent, and periodic acid-methenamine silver. For semiquantitative evaluation, Dr. Yammamoto graded histologic sections for renal injury in a blind fashion. Histologic sections were evaluated for mesangial proliferation, mesangial expansion, interstitial mononuclear cell infiltration, and arteriolar thickening. A grade was given for each section evaluated and the following grades applied for the extent of renal injury: +1 = very mild; +2 = mild; +3 = moderate; and +4 = severe. Histologic sections were evaluated from five animals in each group and an average score for each category determined.
Immunoreactive collagen type IV was assessed in fixed kidney slices. The sections were incubated in 3% (vol/vol) of hydrogen peroxide in PBS containing 0.1% Tween-20 for 15 min to quench endogenous peroxidase activity. The sections were subsequently incubated in goat serum for 1 h at room temperature to block nonspecific binding. Next, the rabbit polyclonal collagen type IV (1:50, Santa Cruz Chemicals) was incubated overnight at room temperature. Peroxidase-conjugated donkey anti-rabbit IgG (1:250) was then applied for 30 min, and the sections were washed with PBS. Chromogen 3,3'-diaminobenzidine was added to the sections for 6 min, washed with distilled water, and counterstained with hematoxylin. The sections were then examined by light microscopy for collagen IV positive staining.
Urinary albumin was assessed as another index for renal injury. Albumin levels were measured by a competitive enzyme immunoassay (Nephrat; Exocell).
Statistical Analyses
All data are presented as mean ± SEM. The significance of differences between groups for the BP and renal vascular data were evaluated with an ANOVA for repeated measures followed by a Duncan’s multiple-range post hoc tests. An unpaired t test was applied to compare the SEH and MEH protein levels, histologic grading, and urinary oxylipid levels. A P value of <0.05 was considered significant.
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Results |
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Plasma and urine CDU and metabolite levels were measured to confirm proper epoxide hydrolase inhibitor treatment. A CDU background signal of unknown origin was detected in control animals (plasma: 1.2 ± 0.2 ng/ml, urine 0.1 ± 0.06 ng/ml) and vehicle-treated angiotensin hypertensive rats (plasma: 1.4 ± 0.3 ng/ml, urine 0.1 ± 0.04 ng/ml). Metabolites of CDU were below detectable limits in the nontreated groups and the aldehyde metabolite, 1-cyclohexyl-3-(12-oxo-dodecyl)-urea (CODU), was below detectable limits in all groups. Angiotensin hypertensive animals treated for 10 d with CDU had significant levels of CDU in the plasma and urine. Plasma CDU levels were 23.1 ± 4.1 ng/ml and the hydroxylic metabolite, 1-cyclohexyl-3-(12-hydroxy-dodecyl)-urea (CHDU) and carboxylic metabolite, 12-(3-cyclohexyl-ureido)-dodecanoic acid (CUDA) averaged 32.9 ± 10.5 ng/ml and 4.1 ± 1.5 ng/ml, respectively, in CDU-treated animals. Ten days of CDU treatment resulted in 10.6 ± 2.4 ng/ml of CDU in the urine and detectable levels of CHDU (0.7 ± 0.3 ng/ml) and CUDA (0.3 ± 0.1 ng/ml).
Plasma arachidonic and linoleic acid metabolite levels at the end of the 20-d angiotensin infusion period are presented in Table 1. The plasma arachidonic and linoleic acid metabolite levels reflect the combination of soluble components, those bound to hydrophobic surfaces, and those incorporated into circulating phospholipids and triglycerides. Interestingly, we observed increased plasma EPOME and decreased DHOME in angiotensin-infused CDU-treated compared with angiotensin-infused corn oil-treated rats. EPOME increased by 126% and DHOME decreased by 60% in angiotensin-infused rats treated with CDU. On the other hand, urinary arachidonic and linoleic acid metabolite levels appear to be a better reflection of the prevailing kidney SEH levels (Table 2). The EPOME:DHOME and EET:DHET ratios were decreased by 50% in the angiotensin-infused group compared with the control group. CDU treatment increased these ratios but had a greater effect on the EET:DHET ratio. EPOME excretion rate increased significantly by 49% in angiotensin-infused CDU-treated rats compared with vehicle-treated angiotensin-infused rats. Unlike plasma levels, the urinary EET and DHET excretion rates had changes consistent with the level of kidney SEH protein expression and SEH inhibition. Although total urinary DHET were not significantly altered, 14,15-DHET levels averaged 2.7 ± 1.5 pmol/d in control and increased to 13.9 ± 3.7 pmol/d in angiotensin-infused animals. CDU treatment for 10 d decreased 14,15-DHET levels to 4.2 ± 2.0 pmol/d in angiotensin hypertension. This finding is consistent with our previously published data in angiotensin-infused rats treated with CDU for 4 d (14). Urinary EET excretion rates decreased in angiotensin-infused rats, while CDU treatment for 10 d increased the urinary EET excretion rate by 94% in angiotensin-infused rats.
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Discussion |
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Epoxides are converted to their corresponding diols by epoxide hydrolase enzymes. In the case of arachidonic epoxygenases, EET dilate the renal vasculature whereas their corresponding DHET are less active or lack vascular activity (3,22,23). Thus, increased conversion of EET to their corresponding diols could reduce their antihypertensive, anti-inflammatory, and antimigratory attributes. Our current studies showed that both MEH and SEH enzymes were expressed in renal microvessels. Although renal microvascular MEH protein levels were not altered, angiotensin hypertension did increase SEH levels in renal microvessels. The ability of CDU to lower BP in angiotensin hypertension confirms that kidney SEH plays a critical role in the development of hypertension.
The present findings also suggest that SEH contributes significantly to the regulation of renal vascular resistance in angiotensin hypertension. Angiotensin hypertensive animals have higher SEH protein levels in renal microvessels. A number of studies by others and our laboratory have demonstrated that angiotensin hypertension is associated with an increased preglomerular resistance and an enhanced reactivity that is selective for angiotensin (24–26). Other animal models of hypertension and human patients with hypertension also exhibit enhanced angiotensin vascular reactivity (27–29). We have also demonstrated that acute elevation of 11,12-EET levels ameliorated the enhanced afferent arteriolar responsiveness to angiotensin in hypertension (30). This finding suggests that angiotensin coupling to vascular EET production may be impaired in angiotensin hypertension. In the study presented here, we present evidence that increased SEH levels may result in increased EET hydration to their less active DHET. Afferent arteriolar functional responses in angiotensin hypertension before and after CDU treatment provide further support for this concept. Like increasing 11,12-EET levels, SEH inhibition could attenuate afferent arteriolar responses to angiotensin in angiotensin hypertension. Thus, SEH inhibition counteracts the deleterious actions of angiotensin hypertension on afferent arteriolar function.
The effect of long-term treatment with an SEH inhibitor on BP was assessed in angiotensin hypertension. Administration of CDU for 10 d significantly lowered BP in angiotensin-infused rats. These data are consistent with a previous report from our laboratory demonstrating that 4 d of CDU lowered BP and increased urinary EET levels in angiotensin hypertension (14). Evidence that SEH is involved in maintenance of BP regulation was demonstrated in SEH gene disrupted mice that have decreased BP (31). A central role for the SEH enzyme in the pathogenesis of hypertension in the spontaneously hypertensive rat (SHR) has also been established (16,32). Yu et al. (16) demonstrated that a single dose of N,N'-dicyclohexylurea (DCU) decreased BP and urinary DHET excretion in the SHR. The effect of DCU on BP in the SHR lasted less than 24 h (16). In the study presented here we demonstrate that administration of an SEH inhibitor over a 10-d period does not lower BP beyond what is observed in the first 4 d. This finding would suggest that chronic treatment of hypertension with CDU will not lower BP to levels observed in control rats.
We conducted additional studies to evaluate the circulating levels of CDU obtained by our treatment and to assess its ability to increase EET levels. We were able to measure CDU and metabolites in the urine and plasma of the angiotensin-infused animals administered CDU. CDU and the hydroxylated metabolite CHDU were the primary plasma constituents found with CHDU at a higher concentration. In contrast, CDU was the main constituent of the urine and CDU metabolites were excreted at low levels. On the basis of these measurements, it is estimated that the CDU plasma concentration was approximately 10 µM, whereas CDU had an average concentration of 32 µM in the urine. These findings confirm the ability of CDU to reach circulating levels necessary for inhibition of the SEH enzyme (15,33).
To further substantiate the efficacy of CDU treatment, we measured urine and plasma arachidonic and linoleic acid metabolites. The linoleic acid epoxygenase metabolites, EPOME, increased in plasma and urine and plasma DHOME decreased at the end of the 10-d CDU treatment of angiotensin hypertensive rats. One cannot rule out the possible contribution of these linoleic acid metabolites to ameliorate renal injury. To date, very little is known about the renal and cardiovascular actions of EPOME and DHOME. 12,13-EPOME and 12,13-DHOME have positive inotropic actions on the isolated rat heart (34). In addition, EPOME infused into conscious rats demonstrated a slight decline in BP but no change in heart rate (34). The renal and cardiovascular actions of the linoleic acid metabolites and their contribution to the effects of SEH inhibition await further exploration. A significant finding of this study is that the measurement of urinary arachidonic acid and linoleic acid metabolites and epoxide to diol ratios appears to be a better indicator of kidney SEH activity. Plasma arachidonic and linoliec acid metabolites as measured in this study may not be a good indicator of SEH activity because total metabolite levels were determined. Nevertheless, consistent with our previous report (14), urinary EET levels were increased two fold and 14,15-DHET levels decreased in angiotensin-infused animals treated with CDU. These findings support the notion that inhibition of the SEH enzyme is likely responsible for the renal and cardiovascular functional changes produced by CDU treatment.
Renal vascular injury was assessed in angiotensin-infused animals treated for 10 d with CDU. Attenuation of renal vascular hypertrophy and glomerular injury was observed in CDU-treated angiotensin hypertensive rats. Increased collagen type IV expression was observed in the glomeruli and tubular epithelial cells of angiotensin-infused rats and deposition of collagen was greatly attenuated by 10 d of CDU treatment. In addition, urinary albumin levels were decreased by CDU treatment and provide additional evidence that end organ damage was decreased in hypertensive animals treated with CDU. Angiotensin infusion in rats has been demonstrated to induce both vascular and tubulointerstitial injury in kidneys (35). Although controversial, clinical studies have found that despite identical reductions in BP, combined angiotensin-converting enzyme (ACE) inhibition and angiotensin type I receptor blocker (ARB) treatment in patients with nephropathy was more effective that either agent alone (36,37). Interestingly, the added beneficial renal and cardiovascular actions of ACE inhibition have been attributed to increased kinin and EDHF levels (38–40). Renal damage has also been linked to kidney specific down regulation of epoxygenase enzymes in the dTGR hypertensive rat and suggests that increasing EET levels may have renal protective actions (41). Our current findings support the notion that increasing EET levels provides protection from end organ damage associated with hypertension. A number of studies have demonstrated anti-inflammatory and cardiovascular protective actions of EET (9–11,42,43). It should be pointed out that the renal protective effects of CDU treatment occurred with a moderate decrease in BP. The effect of the decrease in BP versus other aspects of CDU treatment on renal injury is not known. Taken as a whole, there is ample evidence to support the proposition that increasing EET levels provides renal and cardiovascular protection from hypertension induced end organ damage.
In addition to hypertension, increased arterial pressure is a complicating factor in numerous clinically relevant conditions including diabetes, polycystic kidney disease, and pregnancy (44,45). End organ damage associated with renal and cardiovascular diseases is a major cause of morbidity and mortality. On the basis of a number of recent studies, we tested the postulate that increasing EET levels in vivo through inhibition of SEH is a promising end organ damage therapeutic target. In the study presented here, we demonstrate that chronic administration of the SEH inhibitor CDU lowers arterial BP in angiotensin-dependent hypertension. More importantly, we demonstrated that CDU increased EET and EPOME levels and provided added beneficial protection to the kidney. Therefore, the modulation of endogenous lipid epoxides by SEH inhibitors may have therapeutic benefits for hypertension and end organ damage.
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Acknowledgments |
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s mediates induction of tissue-type plasminogen activator gene transcription by epoxyeicosatrienoic acids. J Biol Chem 276: 15983–15989, 2001 in the rat. Neurosci Lett 310: 141–144, 2001[CrossRef][Medline]
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