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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL
Inducer, Ameliorates Renal Preglomerular Production and Activity of Angiotensin II and Thromboxane A2 in Glycerol-Induced Acute Renal FailureCenter for Cardiovascular Diseases, Texas Southern University, Houston, Texas (Z.Y., H.H., A.O., M.N.); Department of Pathology, Methodist Hospital, Baylor College of Medicine, Houston, Texas (L.T.); and Department of Pathology, Cornell University, New York, New York (L.T.)
Received for publication
March 8, 2007
Accepted
May 8, 2007.
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Abstract |
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(PPAR), a nuclear transcription factor, modulates vascular responses to angiotensin II (AII) or thromboxane A2 (TxA2) via regulation of their gene/receptor. Increased vasoconstriction and deteriorating renal function in glycerol-induced acute renal failure (ARF) may be attributed to down-regulation of PPAR. In this study, we investigated the effect of ciglitazone (CG), a PPAR inducer, on AII and TxA2 production and activity in glycerol-induced ARF. Vascular responses to AII or 9,11-dideoxy-11
,9-epoxymethano prostaglandin F2 (U46619
[GenBank]
), a TxA2 mimetic, were determined in preglomerular vessels following induction of ARF with glycerol. Renal damage and function were assessed in CG-treated (9 nmol/kg for 21 days) rats. PPAR protein expression and activity, which were significantly lower in ARF rats, were enhanced by CG (26 and 30%). CG also increased PPAR mRNA by 67 ± 6%, which was reduced in ARF. In ARF, there was significant tubular necrosis and apoptosis, a 5-fold increase in proteinuria and a 2-fold enhancement in vasoconstriction to AII and U46619.
[GenBank]
CG reduced proteinuria (49 ± 3%), enhanced Na+ (124 ± 35%) and creatinine excretion (92 ± 25%), markedly diminished tubular necrosis, and reduced ARF-induced increase in AII (40 ± 3%) and TxA2 (39 ± 2%) production, the attending increase in vasoconstriction to AII (36 ± 2%) and U46619
[GenBank]
(50 ± 11%), and the increase in angiotensin receptor-1 (AT1) (23 ± 3%) or thromboxane prostaglandin (TP) receptor (13 ± 1%). CG reduced free radical generation by 55 ± 14% while elevating nitrite excretion (65 ± 13%). Our results suggest that enhanced activity of AII and TxA2, increased AT1 or TP receptor expression, and renal injury in glycerol-induced ARF are consequent to down-regulation of PPAR gene. CG ameliorated glycerol-induced effects through maintaining PPAR gene.
; Newaz and Oyekan, 2001). Although the mechanism by which glycerol induces ARF is not clear, this phenomenon is a widely recognized experimental model of myoglobinuric nephropathy, and the renal vasoconstriction seen in the initial phase of the injury is considered to be an important pathogenic event. Other than tubular necrosis, endothelial damage and vasoconstriction may be important contributors to the ensuing ischemia. Increased renal production of angiotensin II (AII) (Yanagisawa et al., 1998) and increased renal angiotensin-converting enzyme (ACE) activity have been reported in ARF (Pedraza-Chaverri et al., 1995). Thromboxane A2 (TxA2), the most potent vasoconstrictor in the biological system, has been shown to be elevated in glycerol-induced ARF (Remuzzi et al., 1992), and selective inhibition of its synthesis protected rats against ARF induced by glycerol (Papanicolaou et al., 1986). These observations raise the possibility of a potential role for AII and TxA2 as mediators of the vasoconstriction and the decrease in renal function seen after glycerol administration.
Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors that belong to the nuclear receptor superfamily and consist of three isoforms named PPAR, PPAR
(or 
), and PPAR. PPAR is expressed in adipose tissue, endothelial cells, and vascular smooth muscle cells (Marx et al., 1999). Because of its critical role in fat metabolism and the clinical efficacy of PPAR activators in diabetes, the role of PPAR in vascular function has been studied extensively in diabetic patients (Vinik et al., 2006) and nondiabetic subjects (Panunti and Fonseca, 2006), and convincing evidence emerged that PPAR activation contributes to vascular function (Blaschke et al., 2006).
Involvement of PPAR in modulating renal vasoconstriction observed in glycerol-induced ARF has not been explored extensively. Previously, it was shown that activation of PPAR suppresses transcription of AT1 receptor (Sugawara et al., 2001) and expression of thromboxane synthase gene (Ikeda et al., 2000). More recently, Toba et al. (2006) suggest that antioxidant and anti-inflammatory effects of PPAR ligands are associated with the inhibition of the expression of ACE (Toba et al., 2006). Recent studies also suggest that PPAR ligands suppress transcription of thromboxane synthase gene (Ikeda et al., 2000) and inhibit TxA2 production and release (Yamazaki et al., 2002; Ray et al., 2006), and both synthetic and endogenous PPAR ligands inhibit transcription of thromboxane prostaglandin (TP) receptors (Coyle et al., 2005; Coyle and Kinsella, 2006). These observations indicate that a role exists for PPAR in the regulation of renal vascular reactivity and thus renal function. In agreement with this, DNA microarray studies and our recent studies showed a down-regulation of PPAR gene in the kidney from ARF rats induced by glycerol (Yoshida et al., 2002; Newaz et al., 2006). Based on these observations, we hypothesize that reduced PPAR is involved in the pathogenesis of glycerolinduced ARF. More precisely, in absence of PPAR there may be exaggerated production and activity of AII or TxA2 that lead to an enhanced renal microvascular reactivity triggering a sequence of events leading to renal failure. In this study, we investigated AII- and TxA2-mediated changes in renal preglomerular vascular reactivity in glycerol-induced ARF and examined the effect of ciglitazone (CG), a PPAR inducer, on AII and TxA2 system in ARF.
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Materials and Methods |
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). Animals. Male Sprague-Dawley rats (250–300 g; Harlan Sprague-Dawley, Houston, TX) were used for this study. The animals were housed under standard conditions of light and dark cycle with free access to food and water. Rats were randomly divided in two groups: control and ARF (animals that received either vehicle or treatment). Treatment groups received CG (9 nmol/kg/day p.o. for 21 days), and the vehicle groups received equal volume of normal saline.
Induction of ARF. ARF was induced in the experimental animals after 21 days of pretreatment with CG or vehicle using the standard method. Glycerol (50% v/v, 8 ml/kg i.m.) was administered as a deep i.m. injection equally distributed to both hind legs. Rats were deprived of food and water for 24 h after glycerol administration. After injecting glycerol, rats were placed in metabolic cages, and urine was collected for 24 h. Blood was collected via cardiac puncture under pentobarbital anesthesia (Na+ pentobarbital, 50 mg/kg i.p.). Kidneys were processed for isolation of renal microvessels and sub-sequent biochemical and molecular biology analysis.
Morphologic Studies. In a separate set of experiments, animals from different experimental groups after the study period were anesthetized with pentobarbital sodium (40 mg/kg i.p.). A laparotomy was performed, and kidneys were prepared for perfusion fixation using formalin (10% v/v in Krebs' buffer). Formalin was infused into the renal artery via the abdominal aorta. After 10 min of perfusion, the kidneys were harvested and subjected to formalin fixation and paraffin embedding followed by 4-µm tissue sections that were stained with H&E, periodic acid-Schiff, and Masson's trichrome stains.
Preparation of Isolated Renal Microvessels. A standard in vitro pressurized arteriole preparation was used to study responses of the renal preglomerular (interlobular) vessels. Preglomerular vessels [intraluminal diameter (ID), 90–120 µm; length, 1 mm] were carefully removed, cleaned, and placed in an organ chamber. The ends of the microvessel were cannulated, and the vessels were pressurized to 80 mm Hg and equilibrated for 45 to 60 min. The tissue was continuously bathed with oxygenated (95% O2/5% CO2) Krebs-Henseleit buffer (118.3 mM NaCl, 4.7 mM KCl, 1.2 mM CaCl2, 1.2 mM MgSO4, 25.0 mM NaHCO3, 1.2 mM KH2PO4, and 5.5 mM glucose) and maintained at 37°C, pH 7.4. Cumulative concentration-response relationships were established for AII (2.5–25 ng/ml) or U46619 [GenBank] , a TxA2 mimetic (10–100 ng/ml). AII (2.5, 5, 10, and 25 ng/ml) and U46619 [GenBank] (10, 50, and 100 ng/ml) were administered randomly, and changes in ID of renal arterioles were recorded. The doses were given 5 to 10 min apart, and a drug-tissue contact time of 3 min was allowed to achieve maximal effect. The drugs were washed off with Krebs' solution before adding another. The organ chamber was placed on the stage of an inverted microscope (Olympus BX40; Olympus, Tokyo, Japan) attached to a video camera, a video monitor, and a calibrated video caliper (video micrometer, model JV6000T; Honeywell Video, Louisville, KY).
Biochemical Analysis. Urinary protein was measured colorimetrically using a kit from Sigma. Urinary excretion of Na+ (UNaV) was determined by flame photometry (Genway FP7; Jenway Ltd, Essex, UK), whereas excretion of nitrite (UNOxV) was determined colorimetrically using the Griess assay. Plasma creatinine and blood urea nitrogen (BUN) were determined by commercial kit purchased from Sigma-Aldrich.
A commercially available enzyme immunoassay kit (Cayman Chemicals, Ann Arbor, MI) was used to determine plasma AII and urinary excretion of thromboxane B2 (TxB2), a stable metabolite of TxA2. Plasma level of 8-isoprostane, an indicator of free radical activity, was also measured by an enzyme immunoassay kit (Cayman Chemicals).
Preparation of Renal Microvascular Extract. After midventral laparotomy, both kidneys were flushed with 20 ml of ice-cold (4°C) Krebs' buffer through the left and right renal arteries. Kidneys were removed and cleaned of fats, and 1- to 2-mm-thick slices were made along the longitudinal axis. Each of these slices was examined under a dissecting microscope, and renal preglomerular vessels (
90–120 µM) were isolated. All the subsequent procedures were performed at 4°C. Vascular tissues were placed in homogenizing buffer (10 mM potassium phosphate, pH 7.0) and homogenized using a Polytron homogenizer (Brinkmann Instruments, Westbury, NY). Cytoplasmic and nuclear fractions were separated by standard differential centrifugation and used for Western blot analysis.
Determination of PPAR Protein Expression and Activity. Equal amounts (40 µg) of cytosolic proteins were loaded onto 12% SDS-polyacrylamide gel and subjected to electrophoresis. Separated proteins were blotted onto polyvinylidene difluoride membranes (GE Healthcare, Little Chalfont, Buckinghamshire, UK). Membranes were then blocked with blocking buffer [5% milk in Tris-buffered saline containing 0.1% Tween (TBST)]. After blocking, the membranes were probed with polyclonal anti-PPAR antibody (1:400, dilution; Santa Cruz Biochemicals) in blocking buffer overnight at 4°C. The membranes were washed extensively with TBST and then incubated with anti-rabbit IgG conjugated to horseradish peroxidase (1:8000 dilution; GE Healthcare) for 1 h. After extensive washing with TBST, membranes were subjected to enhanced chemiluminescence detection using ECL-Plus from GE Healthcare. Signals were captured on X-ray films, and quantitation measurements were performed by using a personal densitometer SI scanner and ImageQuant version 5.0 software from GE Healthcare.
PPAR activation was determined in the nuclear fraction by TransAM PPAR kit from Active Motif Inc. (Carlsbad, CA) following the manufacturer's protocol. In brief, nuclear fractions of renal vascular homogenates were added to an oligonucleotide-coated plate and incubated for 1 h. PPAR antibody was added and incubated for another hour. Anti-IgG horseradish peroxidase was added at this time and incubated for an additional 1 h. At the end of this period, the plate was washed and developing solution added, followed by stop solution. Absorbance was measured within 5 min at 450 nm with a reference wavelength of 655 nm using a plate reader (EL808; Bio-Tek Instruments, Winooski, VT).
Immunoblotting of AT1 and TP Receptor Protein Expression. Western blotting was performed in the cytosolic fraction from the renal vascular homogenate to determine the expression of angiotensin's AT1 receptor protein (50 kDa) and thromboxane TP receptor protein (55 kDa) expression. In brief, 40 µl of protein was electrophoresed onto a 10% SDS-polyacrylamide gel and transferred to a polyvinylidene difluoride membrane. The membranes were probed with rabbit polyclonal antibody to AT1 (catalog no. SC1173, 1:300 dilution) or goat polyclonal antibody to TP receptor (catalog no. SC18377, 1:300 dilution) from Santa Cruz Biochemicals, and the signals were detected by enhanced chemiluminescence (GE Healthcare) after processed with their corresponding secondary antibody SC2301 (anti-rabbit, 1:10,000 dilution) or SC2056 (anti-goat, 1:8000 dilution), respectively.
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Gene Expression by Reverse Transcription-Polymerase Chain Reaction. Renal microvessels were collected under microscope and processed to isolate total RNA using the RNeasy Mini Kit (QIAGEN, Valencia, CA) according to the manufacturer's instructions. Total RNA was quantified, and 100 ng of the RNA was reverse-transcribed using TaqMan reverse transcription reagents at 48°C for 30 min. The cDNA was then amplified using TaqMan Universal polymerase chain reaction (PCR) master mix and Assay on Demand primer probe sets for PPAR and internal control 18S RNA in a real-time PCR system 7300 (Applied Biosystems, Foster City, CA). Each PCR amplification was performed in triplicate wells using the following conditions: 3 min at 95°C, 30 s at 95°C, and 30 s at 60°C through 40 cycles, followed by two cycles of 30 s at 72°C and 1 min at 60°C. The final two cycles were included to perform melt curve analysis to ensure that there were no primer dimers. Negative PCR controls, including omission of reverse transcriptase or omission of cDNA or primers, were used to validate each batch of template before use. Data were collected at the end of 40 cycles and analyzed using the RQ Study software version 1.3 (Applied Biosystems). PPAR gene expression was presented as percentage of 18sRNA.
Statistical Analysis. Response to agonists was expressed as peak change in ID of vessels from their basal values. Data were presented as mean ± S.E.M., and comparisons were made within each group and between groups using analysis of variance and Student's t test for significant differences. In all cases, p 
0.05 was considered significant.
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Effect of CG on Renal Injury and Function in ARF. The i.m. injection of glycerol produces marked proteinuria and deterioration in renal function. The 24-h protein excretion (Fig. 2A) was increased from 44.7 ± 2.8 mg per 24 h in control rats to 295 ± 20 mg per 24 h (p < 0.01) in ARF rats. This increase was associated with a 56 ± 12% (p < 0.05) reduction in creatinine excretion (Fig. 2B). PPAR ligand CG reduced proteinuria by 49 ± 3% (p < 0.05) and blunted the reduction in creatinine excretion in rats treated with glycerol. There was deterioration in renal function in ARF rats as evidenced by a 3-fold decrease in 24-h Na+ (UNaV) excretion (Fig. 3A) and a 2-fold increase in BUN levels (Fig. 3B). CG improved the reduction in UNaV in ARF rats by 124 ± 35% (p < 0.05). Likewise, CG reduced the elevated BUN in ARF rats by 37 ± 3% (p < 0.05).
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Effect of CG on PPAR Expression and Activity. Quantitative reverse transcription-PCR analysis of PPAR mRNA (Fig. 7A) reveals a 46 ± 3% (p < 0.05) reduction of PPAR gene expression in rats treated with glycerol compared with the control rats. CG enhanced PPAR gene expression in ARF rats by 67 ± 6% (p < 0.05). Likewise, PPAR protein expression (Fig. 7B) was attenuated in ARF rats (35 ± 3%; p < 0.05), and this was associated with a reduction (36 ± 3%; p < 0.05) in PPAR activity (Fig. 7C). CG enhanced PPAR protein expression and activity in ARF rats by 26 ± 2% (p < 0.05) and 30 ± 3% (p < 0.05), respectively.
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Discussion |
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in glycerol-induced ARF and that PPAR ligand CG blunted the exaggerated reactivity to vasoconstrictors AII and U46619.
[GenBank]
Typical features of acute tubular necrosis, including tubular casts with features suggestive of myoglobin casts, are noted in kidneys of rats treated with glycerol. Treatment with CG was associated with a marked attenuation of the acute renal injury, including almost abrogation of tubular cell apoptosis/necrosis. This effect was associated not only with reduced endogenous production of AII and TxA2 but also with down-regulation of expression of their respective receptors. In addition, PPAR activation exerts a renoprotective role in this model of ARF as PPAR ligand improves the impaired renal function, a pathological sequence in glycerol-induced ARF probably via induction of PPAR gene.
PPAR, one of the three isoforms of the nuclear receptor superfamily, is known to exert pleiotropic effects. Its effect in regulating vascular function has been examined extensively (Touyz and Schiffrin, 2006), and published data showed that PPAR antagonizes AII effects and PPAR ligand provides superior renal protection (Baylis et al., 2003). The effect of PPAR activation in modulating renal function and renal hemodynamics has also been explored in different disease models, including in diabetic patients (Lansang et al., 2006) and nondiabetic subjects (Panunti and Fonseca, 2006). Data show that the PPAR induction prevented nephropathy, reduced proteinuria, improved macrovascular and microvascular defects, reduced renal oxidative stress, and improved renal tubular function, suggesting a direct relation between PPAR and renal function/injury (Dobrian, 2006).
Impaired renal function and proteinuria are cardinal features of glycerol-induced ARF. Increased muscle necrosis leads to exaggerated creatinine production and elevated BUN. The consequent tubular necrosis and renal vasoconstriction further aggravate the situation, leading to reduced Na+ excretion. Baylis et al. (2003) reported that PPAR agonists provide superior renal protection in terms of glomerular or tubular damage and proteinuria, and this is a direct and protective intrarenal effect (Baylis et al., 2003). In agreement with this, we have shown a renoprotective effect of CG in glycerol-induced ARF, which is evident in renal morphology and in the reduction of urinary protein excretion, an observation supporting the studies of Yotsumoto et al. (2003). This observation is confirmed by the antiproteinuric effect of PPAR ligands mediated via increasing renal tubular cell albumin uptake (Zafiriou et al., 2004) or via transcriptional regulation of nephrin gene (Benigni et al., 2006).
The wide distribution and constitutive expression of PPAR in the renal tubule suggest potentially important regulatory effects on renal function (Dobrian, 2006). These regulatory effects may be attributed to the inhibition of renin-angiotensin system via transcriptional suppression of AT1 receptor (Takeda et al., 2000), leading to reduction in Na+ reabsorption (Kovacs et al., 2002). However, Lansang et al. (2006) suggested that the beneficial effect of PPAR agonists on renal hemodynamics may not be related to an influence on the renin-angiotensin system (Lansang et al., 2006). This notion opens other possibilities for PPAR-mediated improvement in renal function and preventing renal damage. For example, it is possible that PPAR ligands can improve renal function by influencing renal oxidative stress. This speculation is supported by observation that PPAR ligands inhibiting different subunits of NAD(P)H oxidase (Hwang et al., 2005) increase bioavailability of NO (Cernuda-Morollon et al., 2002), a mechanism that may account for their regulation of renal tubular Na+ transport (Dobrian et al., 2003). In this particular case of ARF, it is possible that by activating PPAR CG improves glucose traffic in the skeletal muscle (Zierath et al., 1998) and thus may prevent release of myoglobin and minimize renal damage.
Effective renal vascular reactivity plays a crucial role in maintaining proper renal function. Previously, we have shown increased renal vascular reactivity in isolated perfused kidney from glycerol-induced ARF rats and its amelioration by CG (Newaz et al., 2006). Renal production and activity of AII and TxA2 are critical in regulating vascular tone, and the response to these agonists is more contributory to the process of overall renal function or in developing ARF when they acted on resistance vessels rather than the capacitance vessels. To elucidate this in the present study, we examined renal vascular reactivity to AII and TxA2 specifically in renal preglomerular vessels (resistance vessels) and explored their contribution in the pathogenesis of ARF.
We observed increased preglomerular vascular reactivity to AII and U46619
[GenBank]
in glycerol-induced ARF. This observation is consistent with our previous study in which we showed increased renal vascular response to AII, TxA2, and endothelin-1 in glycerol-induced ARF (Newaz and Oyekan, 2001). Contribution of vasoconstrictors to vascular reactivity could occur via increased endogenous production, increased receptor population, or increases in receptor binding and affinity. It was reported earlier that endogenous production of AII is elevated in glycerol-induced ARF (Yanagisawa et al., 1998) that was associated with an increased AII mRNA, suggesting an up-regulation of angiotensin gene expression. Pedraza-Chaverri et al. (1995) reported an increased ACE activity in glycerol-induced ARF. Likewise, production of endogenous TxA2 has been shown to be increased in glycerol-induced ARF (Remuzzi et al., 1992). These observations corroborate our data showing increased production of endogenous AII and TxA2 and increased expression of their receptors. These observations support the findings of Papanicolaou et al. (1986) who reported reduced TxA2 synthesis and renal protection after selective inhibition of thromboxane synthesis in glycerol-induced ARF (Papanicolaou et al., 1986). A role for PPAR in these effects is supported by the observation that CG reduced vascular response to AII and U46619
[GenBank]
, reduced endogenous production of AII and TxA2, and also reduced expression of AT1 and TP receptor in glycerol-induced ARF. These effects are consistent with previous studies showing that activation of PPAR suppressed transcription of AT1 receptor (Sugawara et al., 2001), reduced AII production by inhibiting ACE (Toba et al., 2006), suppressed transcription of thromboxane synthase gene (Ikeda et al., 2000), inhibited TxA2 production (Yamazaki et al., 2002), and inhibited transcription of TP receptor (Coyle and Kinsella, 2006).
A specific role for PPAR in glycerol-induced ARF is provided by data showing a reduced PPAR protein expression and activity in this model that was associated with renal damage and deteriorating renal function. Quantitative reverse transcription-PCR results from the present study confirm that impairment of PPAR system occurs at gene level and improvement of renal damage and function observed in this model of ARF by PPAR ligands are mediated through induction of PPAR gene. Because increased production of oxygen free radical is a major pathological event in this model of ARF (Dubey et al., 2000) and PPAR gene is susceptible to increased oxidative stress, it is possible that increased free radical-mediated down-regulation of PPAR gene is the sequence of events in glycerol-induced ARF. Because PPAR ligands have been shown to possess direct antioxidant effects (Toba et al., 2006) or indirectly modify NAD(P)H oxidase activity via transcriptional regulation of their individual components (Hwang et al., 2005), it seems that their role in ARF may result from their effects on ROS generation. That may explain the additive effects of PPAR ligand in ARF. Although CG does not have a direct ROS scavenging ability like pioglitazone (Toba et al., 2006), studies have shown cardiovascular antioxidant effects of PPAR ligands (Touyz and Schiffrin, 2006). Our findings of increased plasma isoprostane, reduced renal excretion of NO in ARF, and improvement by CG further confirm this notion and suggest a critical role for PPR in this free radical-inflicted pathology of ARF.
In conclusion, our results suggest that potentiation of renal vascular reactivity to vasoconstrictors, enhanced production of AII and TxA2, increased expression of AT1, and TP receptor associated with renal injury in glycerol-induced ARF are consequent to down-regulation of PPAR gene. We also conclude that CG prevented glycerol-induced renal injury through maintaining an effective PPAR gene expression and PPAR activity.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: ARF, acute renal failure; AII, angiotensin II; ACE, angiotensin-converting enzyme; TxA2, thromboxane A2; PPAR, peroxisome proliferator-activated receptor; CG, ciglitazone, (±)-5-{4-(1-methylcyclohexylmethoxy) benzyl} thiazolidine-2,4-dione; U46619
[GenBank]
, 9,11-dideoxy-11,9-epoxy-methano prostaglandin F2; ID, intraluminal diameter; UNaV, urinary sodium; UNOxV, urinary nitrite; BUN, blood urea nitrogen; TxB2, thromboxane B2; TBST, Tris-buffered saline/Tween 20; PCR, polymerase chain reaction; ROS, reactive oxygen species; TP, thromboxane prostaglandin; AT1, angiotensin receptor-1.
Address correspondence to: Mohammad A. Newaz, Center for Cardiovascular Diseases, Texas Southern University, 3100 Cleburne Avenue, Houston, TX 77004. E-mail: newaz_ma{at}tsu.edu
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