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1.  Epoxyeicosatrienoic Acids, 20-Hydroxyeicosatetraenoic Acid, and Renal Microvascular Function 
The development of pharmacological, genetic, and biochemical tools have allowed for detailed studies to determine the contribution of cytochrome P450 (CYP) metabolites of arachidonic acid to renal microvascular function. Renal microvessels can generate CYP hydroxylase metabolites including 20-hydroxyeicosatetraenoic acid (20-HETE) and CYP epoxygenase metabolites, epoxyeicosatrienoic acids (EETs). 20-HETE constricts afferent arterioles and contributes to renal blood flow autoregulation. EETs act as endothelium-dependent hyperpolarizing factors (EDHFs) on the renal microcirculation. 20-HETE inhibits whereas EETs activate renal microvascular smooth muscle cell large-conductance calcium-activated K+ channels (KCa). Likewise, 20-HETE renal microvascular actions are pro-hypertensive and EET actions are anti-hypertensive. These findings in the renal microvasculature and those of others have provided impetus for the development of enzymatic inhibitors, agonists, and antagonists for 20-HETE and EETs to determine their potential therapeutic value. Initial genetic studies and experimental studies with soluble epoxide hydrolase inhibitors to increase EETs, EET analogs, and 20-HETE inhibitors have demonstrated improved renal microvascular function in hypertension. These findings have demonstrated the important contributions that 20-HETE and EETs play in the regulation of renal microvascular function.
PMCID: PMC3664103  PMID: 23333581
2.  Antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2 transgenic rats is mediated by suppression of the intrarenal renin-angiotensin system 
The present study was undertaken to evaluate the hypothesis that the antihypertensive action of soluble epoxide hydrolase (sEH) inhibition is mediated by an increased availability in intrarenal epoxyeicosatrienoic acids (EETs) with consequent improvement of renal haemodynamic autoregulatory efficiency and of the pressure-natriuresis relationship.Ren-2 transgenic rats (TGR), a model of angiotensin II (ANG II)-dependent hypertension, and normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats were treated with the sEH inhibitor cis-4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]benzoic acid (c-AUCB) for 48 hours. The effects on blood pressure (BP), autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR) and on the pressure-natriuresis relationship in response to stepwise reductions in renal arterial pressure (RAP) were determined.Treatment with c-AUCB did not significantly change BP, renal autoregulation or pressure-natriuresis in normotensive HanSD rats. In contrast, treatment with c-AUCB significantly reduced BP, increased intrarenal bioavailability of EETs, significantly suppressed ANG II levels in TGR. However, treatment with c-AUCB did not significantly improve the autoregulatory efficiency of RBF and GFR in response to reductions of RAP and to restore the blunted pressure-natriuresis relationship in TGR.Taken together, our present data indicate that antihypertensive actions of sEH inhibition in TGR are predominantly mediated via significant suppression of the intrarenal renin-angiotensin system activity.
PMCID: PMC3769696  PMID: 23039246
hypertension; pressure-natriureis; renal blood flow; glomerular filtration rate; cytochrome P450 metabolites; epoxyeicosatrienoic acids; soluble epoxide hydrolase; renin-angiotensin system
3.  Immune and Inflammatory Role in Renal Disease 
Comprehensive Physiology  2013;3(2):957-976.
Chronic and acute renal diseases, irrespective of the initiating cause, have inflammation and immune system activation as a common underlying mechanism. The purpose of this review is to provide a broad overview of immune cells and inflammatory proteins that contribute to the pathogenesis of renal disease, and to discuss some of the physiological changes that occur in the kidney as a result of immune system activation. An overview of common forms of acute and chronic renal disease is provided, followed by a discussion of common therapies that have antiinflammatory or immunosuppressive effects in the treatment of renal disease.
PMCID: PMC3803162  PMID: 23720336
4.  Antihypertensive and renoprotective actions of soluble epoxide hydrolase inhibition in ANG II-dependent malignant hypertension are abolished by pretreatment with L-NAME 
Journal of hypertension  2013;31(2):321-332.
The present study was performed to investigate in a model of malignant hypertension if the antihypertensive actions of soluble epoxide hydrolase (sEH) inhibition are nitric oxide (NO)-dependent.
ANG II-dependent malignant hypertension was induced through dietary administration for 3 days of the natural xenobiotic indole-3-carbinol (I3C) in Cyp1a1-Ren-2 transgenic rats. Blood pressure (BP) was monitored by radiotelemetry and treatment with the sEH inhibitor [cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyl-oxy]-benzoic acid (c-AUCB)] was started 48h before administration of the diet containing I3C. In separate groups of rats, combined administration of the sEH inhibitor and the nonspecific NO synthase inhibitor [Nω-nitro-l-arginine methyl ester (L-NAME)] on the course of BP in I3C-induced and noninduced rats were evaluated. In addition, combined blockade of renin–angiotensin system (RAS) was superimposed on L-NAME administration in separate groups of rats. After 3 days of experimental protocols, the rats were prepared for renal functional studies and renal concentrations of epoxyeicosatrienoic acids (EETs) and their inactive metabolites dihydroxyeicosatrienoic acids (DHETEs) were measured.
Treatment with c-AUCB increased the renal EETs/DHETEs ratio, attenuated the increases in BP, and prevented the decreases in renal function and the development of renal damage in I3C-induced Cyp1a1-Ren-2 rats. The BP lowering and renoprotective actions of the treatment with the sEH inhibitor c-AUCB were completely abolished by concomitant administration of L-NAME and not fully rescued by double RAS blockade without altering the increased EETs/DHETEs ratio.
Our current findings indicate that the antihypertensive actions of sEH inhibition in this ANG II-dependent malignant form of hypertension are dependent on the interactions of endogenous bioavailability of EETs and NO.
PMCID: PMC3773167  PMID: 23307303
cytochrome P-450 metabolites; epoxyeicosatrienoic acids; malignant hypertension; nitric oxide; nitric oxide synthase; renin–angiotensin system; soluble epoxide hydrolase
5.  Afferent arteriolar responses to β,γ-methylene ATP and 20-HETE are not blocked by ENaC inhibition 
Physiological Reports  2013;1(4):e00082.
Afferent arteriolar myogenic and tubuloglomerular feedback responses are critical for the proper maintenance of renal hemodynamics and water and electrolyte homeostasis. Adenosine triphosphate (ATP) P2X receptor activation and 20-hydroxyeicosatetraenoic acids (20-HETE) have been implicated in afferent arteriolar autoregulatory responses. Besides these two participants, members of the degenerin/epithelial Na+ channel (DEG/ENaC) family have been demonstrated to play a pivotal role in the afferent arteriolar myogenic response. The aim of this study was to determine if ENaC contributes to P2X receptor- or 20-HETE-mediated afferent arteriolar vasoconstriction. As previously demonstrated, afferent arteriolar diameter responses to increasing perfusion pressure from 100 to 160 mmHg were abolished by ENaC inhibitors amiloride or benzamil. Afferent arteriolar diameter decreased by 29% under control conditions and by 1% and 5% in the presence of amiloride or benzamil, respectively. The P2X receptor agonist β,γ-methylene ATP decreased afferent arteriolar diameter by 3 ± 1%, 7 ± 1%, 12 ± 2%, and 17 ± 3% in response to 0.1, 1, 10, and 100 μmol/L, respectively. ENaC inhibition did not alter the afferent arteriolar vasoconstrictor response to the P2X receptor agonist β,γ-methylene ATP. Like P2X receptor activation, 20-HETE dose-dependently decreased afferent arteriolar diameter and this vasoconstrictor response was not altered by the presence of ENaC inhibitors amiloride or benzamil. These results suggest that DEG/ENaC channels are required for afferent arteriolar autoregulatory responses; however, DEG/ENaC channels do not contribute to P2X receptor- or 20-HETE-mediated afferent arteriolar vasoconstriction.
PMCID: PMC3804346  PMID: 24159379
Autoregulation; eicosanoids; kidney; myogenic response; purinergic receptors
6.  Inhibition of soluble epoxide hydrolase improves the impaired pressure–natriuresis relationship and attenuates the development of hypertension and hypertension-associated end-organ damage in Cyp1a1-Ren-2 transgenic rats 
Journal of hypertension  2011;29(8):1590-1601.
In the present study, we compared the effects of treatment with the novel soluble epoxide hydrolase (sEH) inhibitor (c-AUCB) with those of the AT1 receptor antagonist losartan on blood pressure (BP), autoregulation of renal blood flow (RBF) and on glomerular filtration rate (GFR) and the pressure–natriuresis relationship in response to stepwise reduction in renal arterial pressure (RAP) in Cyp1a1-Ren-2 transgenic rats.
Hypertension was induced in Cyp1a1-Ren-2 rats through dietary administration for 11 days of the natural xenobiotic indole-3-carbinol (I3C) which activates the renin gene. Treatment with c-AUCB and losartan was started 48 h before initiating administration of the diet containing I3C. Rats were prepared for renal functional studies to evaluate in-vivo renal autoregulatory efficiency when RAP was gradually decreased by an aortic clamp.
I3C administration resulted in the development of severe hypertension which was associated with markedly lower basal RBF and GFR and substantially impaired autoregulatory efficiency as well as a suppression of the pressure–natriuresis relationship when compared with noninduced rats. Treatment with c-AUCB significantly decreased BP, improved autoregulatory efficiency of RBF and GFR and the slope of pressure–natriuresis relationship. Treatment with losartan completely prevented the impaired autoregulation and pressure–natriuresis relationship as well as the development of hypertension in I3C-induced rats.
Our present findings indicate that chronic treatment with the sEH inhibitor c-AUCB substantially attenuates the development of malignant hypertension in I3C-induced rats likely via improvement of the renal autoregulatory efficiency and the pressure–natriuresis relationship.
PMCID: PMC3777565  PMID: 21720266
AT1 receptor antagonist; cytochrome P-450 metabolites; epoxyeicosatrienoic acids; malignant hypertension; renal autoregulation; renin-angiotensin system; sodium excretion; soluble epoxide hydrolase
7.  Soluble epoxide hydrolase inhibition and peroxisome proliferator activated receptor γ agonist improve vascular function and decrease renal injury in hypertensive obese rats 
Cardiometabolic syndrome occurs with obesity and consists of pathophysiological factors that increase the risk for cardiovascular events. Soluble epoxide hydrolase inhibition (sEHi) is a novel therapeutic approach that exerts renal and cardiovascular protection. Although sEHi as a therapeutic approach is promising, it could be more effective for the treatment of cardiometabolic syndrome when combined with peroxisome proliferator activated receptor γ (PPARγ) agonists. We hypothesized that the PPARγ agonist, rosiglitazone in combination with a sEHi (tAUCB) will provide synergistic actions to decrease blood pressure, improve vascular function, decrease inflammation, and prevent renal damage in spontaneously hypertensive obese rats (SHROB). SHROB were treated with rosiglitazone, tAUCB or the combination of tAUCB and rosiglitazone for four-weeks and compared with spontaneously hypertensive (SHR) and Wistar–Kyoto (WKY) rats. Blood pressure increased in SHROB (164 ±7 mmHg) and decreased 10 mmHg when treated with rosiglitazone, tAUCB, or tAUCB and rosiglitazone. Mesenteric artery dilation to the KATP channel opener pinacidil was attenuated in SHROB (EMax = 77 ±7%), compared with WKY (EMax = 115 ±19) and SHR (EMax = 93 ±12%). Vasodilation to pinacidil was improved by rosiglitazone (EMax = 92 ±14%) but not tAUCB. Renal macrophage infiltration increased in SHROB and significantly decreased with rosiglitazone or tAUCB and rosiglitazone treatment. Albuminuria was increased in SHROB (90 ±20 mg/d) and was significantly decreased by the combination of tAUCB and rosiglitazone (37 ±9 mg/d). Glomerular injury in SHROB was also significantly decreased by tAUCB and rosiglitazone. These results indicate that even though sEHi or PPARγ agonist have benefits when used individually, the combination is more beneficial for the multidisease features in cardiometabolic syndrome.
PMCID: PMC3613242  PMID: 23354399
epoxyeicosatrienoic acid; kidney; metabolic syndrome
8.  Captopril attenuates hypertension and renal injury induced by the vascular endothelial growth factor inhibitor sorafenib 
Vascular endothelial growth factor inhibitors (VEGFi) are known to cause hypertension and renal injury that severely limits their use as an anticancer therapy. We hypothesized that the angiotensin-converting enzyme inhibitor captopril not only prevents hypertension, but also decreases renal injury caused by the VEGFi sorafenib.Rats were administered sorafenib (20 mg/kg per day) alone or in combination with captopril (40 mg/kg per day) for 4 weeks. Sorafenib administration increased blood pressure, which plateaued by day 10.Concurrent treatment with captopril for 4 weeks resulted in a 30 mmHg decrease in blood pressure compared with sorafenib alone (155 ± 5 vs 182 ± 6 mmHg, respectively; P < 0.05). Furthermore, concurrent captopril treatment reduced albuminuria by 50% compared with sorafenib alone (20 ± 8 vs 42 ± 9 mg/day, respectively; P < 0.05) and reduced nephrinuria by eightfold (280 ± 96 vs 2305 ± 665 μg/day, respectively; P < 0.05). Glomerular injury, thrombotic micro-angiopathy and tubular cast formation were also decreased in captopril-treated rats administered sorafenib. Renal autoregulatory efficiency was determined by evaluating the afferent arteriolar constrictor response to ATP. Sorafenib administration attenuated the vasoconstriction to ATP, whereas concurrent captopril treatment improved ATP reactivity.In conclusion, captopril attenuated hypertension and renal injury and improved renal autoregulatory capacity in rats administered sorafenib. These findings indicate that captopril treatment, in addition to alleviating the detrimental side-effect of hypertension, decreases the renal injury associated with anticancer VEGFi therapies such as sorafenib.
PMCID: PMC3613249  PMID: 22443474
afferent arterioles; albuminuria; glomerular injury; hypertension.nephrinuria; vascular endothelial growth factor inhibitors
9.  Cytochrome P450 eicosanoids and cerebral vascular function 
The eicosanoids 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs), which are generated from the metabolism of arachidonic acid by cytochrome P450 (CYP) enzymes, possess a wide array of biological actions, including the regulation of blood flow to organs. 20-HETE and EETs are generated in various cell types in the brain and cerebral blood vessels, and contribute significantly to cerebral blood flow autoregulation and the coupling of regional brain blood flow to neuronal activity (neurovascular coupling). Investigations are beginning to unravel the molecular and cellular mechanisms by which these CYP eicosanoids regulate cerebral vascular function and the changes that occur in pathological states. Intriguingly, 20-HETE and the soluble epoxide hydrolase (sEH) enzyme that regulates EET levels have been explored as molecular therapeutic targets for cerebral vascular diseases. Inhibition of 20-HETE, or increasing EET levels by inhibiting the sEH enzyme, decreases cerebral damage following stroke. The improved outcome following cerebral ischaemia is a consequence of improving cerebral vascular structure or function and protecting neurons from cell death. Thus, the CYP eicosanoids are key regulators of cerebral vascular function and novel therapeutic targets for cardiovascular diseases and neurological disorders.
PMCID: PMC3613250  PMID: 21356152
10.  Soluble epoxide hydrolase inhibition exhibits antihypertensive actions independently of nitric oxide in mice with renovascular hypertension 
Kidney & blood pressure research  2012;35(6):595-607.
The present study was performed to examine whether the blood pressure (BP)-lowering effects of soluble epoxide hydrolase (sEH) inhibition in two-kidney, one-clip (2K1C) Goldblatt hypertension are nitric oxide (NO)-dependent.
Mice lacking the endothelial NO synthase (eNOS) gene (eNOS −/−) and their wild-type controls (eNOS +/+) underwent clipping of one renal artery. BP was monitored by radiotelemetry and the treatment with the sEH inhibitor cis-4-[4-(3-adamantan-1-yl-ureido)cyclo-hexyl-oxy]-benzoic acid (c-AUCB) was initiated on day 25 after clipping and lasted for 14 days. Renal concentrations of epoxyeicosatrienoic acids (EETs) and their inactive metabolite dihydroxyeicosatrienoic acids (DHETs) were measured in the nonclipped kidney. Renal NO synthase (NOS) activity was determined by measuring the rate of formation of L-[14C]citruline from L-[14C] arginine.
Treatment with the sEH inhibitor elicited similar BP decreases that were associated with increases in daily sodium excretion in 2K1C eNOS+/+ as well as 2K1C eNOS−/− mice. In addition, treatment with the sEH inhibitor increaseds the ratio of EETs/DHETEs in the nonclipped kidney of 2K1C eNOS+/+ as well as 2K1C eNOS−/− mice. Treatment with the sEH inhibitor did not alter renal NOS activity in any of the experimental groups.
Collectively, our present data suggest that the BP-lowering effects of chronic sEH inhibition in 2K1C mice are mainly associated with normalization of the reduced availability of biologically active EETs in the nonclipped kidney and their direct natriuretic actions.
PMCID: PMC3604982  PMID: 22948718
two-kidney one-clip Goldblatt hypertension; cytochrome P-450 metabolites; epoxyeicosatrienoic acids; soluble epoxide hydrolase; renin-angiotensin system; sodium excretion; nitric oxide; endothelial nitric oxide synthase
American journal of hypertension  2011;24(7):816-821.
Angiotension receptor blockers (ARB), telmisartan and valsartan were compared for renal protection in spontaneously hypertensive rats (SHR) fed high fat diet. We hypothesized that in cardiometabolic syndrome, telmisartan an ARB with PPAR-γ activity will offer better renal protection.
SHR were fed either normal (SHR-NF, 7% fat) or high fat (SHR-HF, 36% fat) diet and treated with an ARB for 10 weeks.
Blood pressure was similar between SHR-NF (190±3 mmHg) and SHR-HF (192±4 mmHg) at the end of the 10 week period. Telmisartan and valsartan decreased blood pressure to similar extents in SHR-NF and SHR-HF groups. Body weight was significantly higher in SHR-HF (368±5g) compared to SHR-NF (328±7g). Telmisartan but not valsartan significantly reduced the body weight gain in SHR-HF. Telmisartan was also more effective than valsartan in improving glycemic and lipid status in SHR-HF. Monocyte chemoattractant protein-1 (MCP-1), an inflammatory marker, was higher in SHR-HF (24±2 ng/d) compared to SHR-NF (14±5 ng/d). Telmisartan reduced MCP-1 excretion in both SHR-HF and SHR-NF to a greater extent than valsartan. An indicator of renal injury, urinary albumin excretion increased to 85±8 mg/d in SHR-HF compared to 54±9 mg/d in SHR-NF. Telmisartan (23±5 mg/d) was more effective than valsartan (45±3 mg/d) in lowering urinary albumin excretion in SHR-HF. Moreover, telmisartan reduced glomerular damage to a greater extent than valsartan in the SHR-HF.
Collectively, our data demonstrate that telmisartan was more effective than valsartan in reducing body weight gain, renal inflammation, and renal injury in a rat model of cardiometabolic syndrome.
PMCID: PMC3721747  PMID: 21415842
cardiometabolic syndrome; renin-angiotensin system; high fat diet; hypertension; inflammation; renal injury
12.  Inhibition of soluble epoxide hydrolase by cis-4-[4-(3-adamantan-1-yl-ureido)cyclohexyl-oxy]benzoic acid exhibits antihypertensive and cardioprotective actions in transgenic rats with angiotensin II-dependent hypertension 
The present study was undertaken to evaluate the effects of chronic treatment with cis-4-[4-(3- adamantan-1-yl-ureido)cyclohexyl-oxy]benzoic acid (c-AUCB), a novel inhibitor of soluble epoxide hydrolase (sEH), which is responsible for the conversion of biologically active epoxyeicosatrienoic acids (EETs) to biologically inactive dihydroxyeicosatrienoic acids (DHETEs), on blood pressure (BP) and myocardial infarct size in male heterozygous Ren-2 transgenic rats (TGR) with established hypertension. Normotensive Hannover Sprague-Dawley (HanSD) rats served as controls. Myocardial ischemia was induced by coronary artery occlusion. Systolic BP was measured in conscious animals by tail-plethysmography. c-AUCB was administrated in drinking water. Renal and myocardial concentrations of EETs and DHETEs served as markers of internal production of epoxygenase metabolites. Chronic treatment with c-AUCB, which resulted in significant increases in the availability of biologically active epoxygenase metabolites in TGR – assessed as the ratio of EETs/DHETEs – was accompanied by a significant reduction in BP and significantly reduced infarct size in TGR as compared with untreated TGR. The cardioprotective action of c-AUCB treatment was completely prevented by acute administration of a selective EETs antagonist (14,15-epoxyeicosa5(Z)-enoic acid), supporting the notion that the improved cardiac ischemic tolerance conferred by sEH inhibition is mediated by EETs actions at the cellular level. These findings indicate that chronic inhibition of sEH exhibits antihypertensive and cardioprotective actions in this transgenic model of angiotensin II-dependent hypertension.
PMCID: PMC3528350  PMID: 22324471
hypertension; angiotensin II; kidney; epoxyeicosatrienoic acids; soluble epoxide hydrolase inhibitor; myocardial ischemia/reperfusion injury
13.  Epoxides and Soluble Epoxide Hydrolase in Cardiovascular Physiology 
Physiological reviews  2012;92(1):101-130.
Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites that importantly contribute to vascular and cardiac physiology. The contribution of EETs to vascular and cardiac function is further influenced by soluble epoxide hydrolase (sEH) that degrades EETs to diols. Vascular actions of EETs include dilation and angiogenesis. EETs also decrease inflammation and platelet aggregation and in general act to maintain vascular homeostasis. Myocyte contraction and increased coronary blood flow are the two primary EET actions in the heart. EET cell signaling mechanisms are tissue and organ specific and provide significant evidence for the existence of EET receptors. Additionally, pharmacological and genetic manipulations of EETs and sEH have demonstrated a contribution for this metabolic pathway to cardiovascular diseases. Given the impact of EETs to cardiovascular physiology, there is emerging evidence that development of EET-based therapeutics will be beneficial for cardiovascular diseases.
PMCID: PMC3613253  PMID: 22298653
14.  Targeting Epoxides for Organ Damage in Hypertension 
Epoxyeicosatrienoic acids (EETs) are synthesized from arachidonic acid and EETs have a number of beneficial cardiovascular actions. This has led to the concept that EETs and its metabolic pathway can be therapeutically targeted for hypertension and other cardiovascular diseases. One approach has been to prevent the conversion of EETs to their inactive diols by inhibiting the soluble epoxide hydrolase (sEH) enzyme. Inhibition of sEH has been demonstrated to decrease blood pressure in certain experimental models of hypertension, decrease inflammation, and protect organs from damage associated with hypertension and other cardiovascular diseases. The development of sEH inhibitors has reached the point where they are being evaluated in humans. A second therapeutic approach has been to develop EET agonists. EET agonists have been essential for determining the structure function relationship for EETs and determining cell-signaling mechanisms by which EETs exert their cardiovascular actions. More recently, EET agonists have been administered chronically to experimental animal models of hypertension and metabolic syndrome and have been demonstrated to decrease blood pressure, improve insulin signaling, and improve vascular function. These experimental findings provide evidence for sEH inhibitors and EET agonists as a therapeutic approach for cardiovascular diseases, hypertension, and the associated end organ damage.
PMCID: PMC3071608  PMID: 20531214
15.  Epoxyeicosatrienoic Acid Analogs and Vascular Function 
Current medicinal chemistry  2010;17(12):1181-1190.
Arachidonic acid metabolites, eicosanoids, are key contributors to vascular function and improper eicosanoid regulation contributes to the progression of cardiovascular diseases. Epoxyeicosatrienoic acids (EETs) are synthesized from arachidonic acid by epoxygenase enzymes to four regioisomers, 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET. These EETs have interesting beneficial effects like vasodilation, anti-inflammation, and anti-platelet aggregation that could combat cardiovascular diseases. There is mounting evidence that each regioisomeric EET may have unique vascular effects and that the contribution of individual EETs to vascular function differs from organ to organ. Over the past decade EET analogs and antagonists have been synthesized to determine EET structure function relationships and define the contribution of each regioisomeric EET. A number of studies have demonstrated that EET analogs induce vasodilation, lower blood pressure and decrease inflammation. EET antagonists have also been used to demonstrate that endogenous EETs contribute importantly to cardiovascular function. This review will discuss EET synthesis, regulation and physiological roles in the cardiovascular system. Next we will focus on the development of EET analogs and what has been learned about their contribution to vascular function. Finally, the development of EET antagonists and how these have been utilized to determine the cardiovascular actions of endogenous epoxides will be discussed. Overall, this review will highlight the important knowledge garnered by the development of EET analogs and their possible value in the treatment of cardiovascular diseases.
PMCID: PMC2855336  PMID: 20158473
epoxyeicosatrienoic acids; endothelium derived hyperpolarizing factor; cardiovascular; inflammation; analogs; agonist and antagonist
16.  Glomerular Expression of Kidney Injury Molecule-1 and Podocytopenia in Diabetic Glomerulopathy 
American Journal of Nephrology  2011;34(3):268-280.
Studies have shown that kidney injury molecule-1 (KIM-1) is upregulated in damaged renal proximal tubules. In this study, we examined KIM-1 expression in glomerular epithelial cells in diabetic glomerulopathy.
Renal histology, immunostaining and Western blot for protein level, and real-time PCR for mRNA expression of KIM-1 and podocyte markers were evaluated in untreated or losartan-treated Zucker lean (Fa/+) and Zucker diabetic fatty (Fa/Fa) rats.
The diabetic rats showed an increased glomerular expression of KIM-1. KIM-1 staining was localized primarily in the hyperplastic parietal epithelium of Bowman's capsule in the early stages of diabetes with subsequent increase in KIM-1-positive cells in the glomerular tuft in the more advanced stages. The increase in glomerular KIM-1 was associated with a decrease in podocytes in Fa/Fa rats. Antiproteinuric treatment with losartan attenuated podocytopenia and decreased renal expression of KIM-1 in treated diabetic rats. In an in vitro study, albumin overload increased KIM-1 protein in the primary cultures of rat glomerular epithelial cells.
These results show that glomerular KIM-1 expression was increased, in proportion to the extent of proteinuria and podocytopenia in the diabetic animals, supporting that KIM-1 could be used as a potential biomarker for glomerular injury in proteinuric kidney disease.
PMCID: PMC3169370  PMID: 21822010
Albuminuria; Kidney injury molecule-1; Parietal epithelial cells; Podocytes; Glomerulopathy
17.  Mechanisms involved in oleamide-induced vasorelaxation in rat mesenteric resistance arteries 
European journal of pharmacology  2009;607(1-3):143-150.
Fatty acid amides are a new class of signaling lipids that have been implicated in diverse physiological and pathological conditions. Oleamide is a fatty acid amide that induces vasorelaxation. Here, we investigated the mechanisms behind the vasorelaxation effect of oleamide in rat mesenteric resistance arteries. Oleamide-induced concentration dependent (0.01 μM–10μM) vasorelaxation in mesenteric resistance arteries. This relaxation was unaffected by the presence of the fatty acid amide hydrolase (FAAH) inhibitors. The cannabinoid type 1 (CB1) receptor antagonist, AM251 and the non-CB1/CB2 cannabinoid receptor antagonist, O-1918, attenuated the oleamide vasodilatory response, however the cannabinoid CB2 receptor antagonist, AM630, did not affect the vascular response. Moreover, inhibition of the transient receptor potential vanilloid (TRPV) 1 receptor with capsazepine shifted the oleamide-induced vasorelaxation response to the right. In agreement with the vascular functional data, the cannabinoid CB1 and TRPV1 receptor proteins were expressed in mesenteric resistance arteries but cannabinoid CB2 receptors and the FAAH enzyme were not. In endothelium-denuded arteries, the oleamide-mediated vasorelaxation was attenuated and cannabinoid CB1 or non-CB1/CB2 cannabinoid receptor blockade did not further reduce the dilatory response whereas TRPV1 antagonism further decreased the response. These findings indicate that cannabinoid receptors on the endothelium and endothelium-independent TRPV1 receptors contribute to the oleamide vasodilatory response. Taken together, these results demonstrate that the oleamide-induced vasorelaxation is mediated, in part, by cannabinoid CB1 receptors, non-CB1/CB2 cannabinoid receptors, and TRPV1 receptors in rat mesenteric resistance arteries. These mechanisms are overlapping in respect to oleamide-induced mesenteric resistance artery dilation.
PMCID: PMC2664517  PMID: 19326479
oleamide; cannabinoid receptors; endothelium; fatty acid amide; mesenteric arteries
18.  Eicosanoids and Renal Damage in Cardiometabolic Syndrome 
Obesity, hypertension and type 2 diabetes are major contributing factors to the increase in the number of patients that have chronic kidney disease. The clustering of visceral obesity and cardiovascular risk factors has been designated metabolic syndrome or cardiometabolic syndrome. Cardiometabolic syndrome is associated with a complex systemic inflammatory state that has been implicated in medically important complications including endothelial dysfunction. Inflammation, endothelial dysfunction, and insulin resistance are interrelated and have reciprocal relationships that link cardiovascular and metabolic diseases. Ultimately, cardiometabolic syndrome increases the risk for cardiovascular events and end organ damage. Although the number of patients with cardiometabolic syndrome is escalating, therapeutic approaches have not been developed that provide protection to the kidney. Eicosanoids are altered in cardiometabolic syndrome and contribute the progression of renal injury. The anti-hypertensive and anti-inflammatory actions of epoxides and soluble epoxide hydrolase inhibitors make these attractive eicosanoid therapeutic targets for chronic kidney disease in patients with cardiometabolic syndrome.
PMCID: PMC3348552  PMID: 18248310
kidney; epoxyeicosatrienoic acids; epoxide hydrolase; obesity; cytokines; inflammation
19.  Chemokine Receptor CCR2b Inhibition Provides Renal Protection in Angiotensin II-Salt Hypertension 
Hypertension  2007;50(6):1069-1076.
The present study was designed to determine if chemokine receptor 2b (CCR2b) contributes to the development of renal injury in salt-sensitive angiotensin II (ANG) hypertension. Rats were infused with ANG and fed a high-salt diet (HS) for 14 days. Rats were divided into four groups: HS, HS administered the CCR2b antagonist, RS102895, ANG/HS hypertensive, and ANG/HS hypertensive administered RS102895. CCR2b inhibition slowed the progression of blood pressure elevation during the first week of ANG/HS hypertension; however, it did not alter blood pressure in the HS group. At two weeks, arterial pressure was not significantly different between ANG/HS and ANG/HS hypertensive rats administered RS102895. Renal cortical NFκB activity increased in ANG/HS hypertension compared to HS group (0.11 ± 0.006 vs. 0.08 ± 0.003 ng activated NFκB/μg protein) and RS102895 treatment lowered NFκB activity in ANG/HS hypertension (0.08 0.005 ng activated NFκB/μg protein). Renal TNF-alpha and ICAM-1 expression increased and Cyp2c23 expression decreased in ANG/HS hypertension compared to HS group and CCR2b inhibition reduced TNF-alpha and ICAM-1 and increased Cyp2c23 expression. Histological immunostaining revealed increased renal monocyte and macrophage infiltration in ANG/HS hypertensive rats with decreased infiltration in rats receiving RS102895 treatment. Albuminuria and cortical collagen staining also increased in ANG/HS hypertensive rats and RS102895 treatment lowered these effects. Afferent arteriolar autoregulatory responses to increasing renal perfusion pressure were blunted in ANG/HS hypertension and RS102895 treatment improved this response. These data suggest that CCR2b inhibition protects the kidney in hypertension by reducing inflammation and delaying the progression of hypertension.
PMCID: PMC2491337  PMID: 17938380
Kidney; inflammation; hypertension; angiotensin; MCP-1; CCR2b; chemokines
20.  20-HETE & Angiotensin – A Positive Feedback System to Cause Hypertension 
Hypertension  2010;56(5):822-823.
PMCID: PMC2998348  PMID: 20837886
21.  Combined inhibition of 20-hydroxyeicosatetraenoic acid formation and of epoxyeicosatrienoic acids degradation attenuates hypertension and hypertension-induced end-organ damage in Ren-2 transgenic rats 
Recent studies have shown that the renal cytochrome P-450 metabolites of arachidonic acid: the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE), and the vasodilator epoxyeicosatrienoic acids (EETs) play an important role in the pathophysiology of angiotensin II (ANG II)-dependent forms of hypertension and the associated target organ damage. The present studies were performed in Ren-2 renin transgenic rats (TGR) to evaluate the effects of chronic selective inhibition of 20-HETE formation or elevation of the level of EETs, alone or in combination, on the course of hypertension and hypertension-associated end-organ damage. Both young (30 days of age) prehypertensive TGR and adult (190 days of age) TGR with established hypertension were examined. Normotensive Hannover Sprague-Dawley (HanSD) rats served as controls. The rats were treated with N-methylsulfonyl-12,12-dibromododec-11-enamide to inhibit 20-HETE formation and/or with N-cyclohexyl-N-dodecyl urea to inhibit soluble epoxide hydrolase and prevent degradation of EETs. Inhibition in TGR rats of 20-HETE formation combined with enhanced bioavailability of EETs attenuated the development of hypertension, cardiac hypertrophy, proteinuria, glomerular hypertrophy and sclerosis as well as renal tubulointerstitial injury. This was also associated with an attenuation of the responsiveness of the systemic and renal vascular beds to ANG II without modifying their responses to norepinephrine. Our data suggest that altered production and/or action of 20-HETE and EETs plays a permissive role in the development of hypertension and hypertension-associated end-organ damage in this model of ANG II-dependent hypertension. This information provides a basis for a search of new therapeutic approaches to the treatment of hypertension.
PMCID: PMC2854172  PMID: 20050826
cytochrome P-450 metabolites; renin-angiotensin system; hypertension; end-organ damage; soluble epoxide hydrolase
22.  Intrarenal CYP-450 metabolites of arachidonic acid in the regulation of the nonclipped kidney function in two-kidney, one-clip Goldblatt hypertensive rats 
Journal of hypertension  2010;28(3):582-593.
The contribution of cytochrome P-450 (CYP) metabolites of arachidonic acid: epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE) in the regulation of nonclipped kidney function in two-kidney, one-clip (2K1C) Goldblatt hypertensive rats during the phases of initial and stable hypertension (7 or 27 days after clipping, respectively) were investigated.
Male Hannover-Sprague Dawley rats had the right renal artery clipped or had a sham-operation. Urinary excretion of EETs, their inactive metabolites (DHETEs), and 20-HETE were measured. Intrarenal CYP protein expression and the activities of epoxygenase, ω-hydroxylase and soluble epoxide hydrolase (sEH) were also determined.
The responses of renal hemodynamics and electrolyte excretion of the non-clipped kidney to left renal artery infusions of inhibitors of EETs or 20-HETE formation (MS-PPOH and DDMS, respectively) were measured.
In 2K1C rats the urinary EETs excretion was lower and 20-HETE excretion was higher than in sham-operated animals. Intrarenal inhibition of EETs significantly decreased renal hemodynamics and sodium excretion in sham-operated but not in 2K1C rats. Intrarenal inhibition of 20-HETE decreased sodium excretion in sham-operated rats but elicited increases in renal hemodynamics and sodium excretion in 2K1C rats.
The results indicate that the nonclipped kidney of Goldblatt 2K1C rats in the phase of sustained hypertension exhibits decreased intrarenal EETs and elevated 20-HETE levels as compared with the kidney of sham-operated animals. This suggests that altered production and action of CYP-derived metabolites in this phase contributes to the mechanism of Goldblatt 2K1C hypertension.
PMCID: PMC2855337  PMID: 19940786
two-kidney one-clip Goldblatt hypertension; cytochrome P-450 metabolites; epoxyeicosatrienoic acids; 20-hydroxyeicosatetraenoic acid; renin-angiotensin system; renal function
Obesity and hypertension are the two major risk factors that contribute to the progression of end-stage renal disease. To examine whether hypertension further exacerbates oxidative stress and vascular dysfunction and inflammation in obese rats, four groups of male Sprague Dawley rats were fed either normal (7% fat) or high fat (36% fat) diet for 6 weeks and osmotic pumps were implanted to deliver angiotensin II (ANG) or vehicle for four additional weeks. High fat diet treatment did not alter ANG-induced hypertension compared to normal diet (174±6 vs. 170±5 mmHg, respectively). High fat diet treatment increased body weight gain and plasma leptin levels and induced insulin resistance in normotensive and ANG hypertensive rats. Plasma TBARs, a measure of oxidative stress, was elevated in high fat diet fed rats compared to control (11.2±1 vs. 8.4±1 nmol/ml, respectively) and was further increased in ANG hypertensive rats fed high fat diet (18.8±2.2 nmol/ml). Urinary nitrite excretion was also decreased in rats fed high fat diet with or without ANG infusion compared to control. Afferent arteriolar relaxation to acetylcholine was impaired in high fat fed rats with or without ANG infusion. Renal cortical TNF-α, COX-2, and phospho-IKK expression increased in high fat diet compared to normal diet fed rats. The increases in phospho-IKK and COX-2 expression were further elevated in ANG hypertensive rats fed high fat diet. These data suggest that ANG-induced hypertension exacerbates oxidative stress and renal inflammation without further impairment in vascular dysfunction in high fat diet-induced obesity.
PMCID: PMC2842481  PMID: 19728860
Obesity; oxidative stress; inflammation; hypertension; vascular dysfunction
24.  Soluble Epoxide Hydrolase as a Therapeutic Target for Cardiovascular Diseases 
Nature reviews. Drug discovery  2009;8(10):794-805.
Cardiovascular effects of epoxyeicosatrienoic acids (EETs) include vasodilation, vascular smooth muscle cell anti-migratory actions, and anti-inflammatory actions. These endogenous lipid mediators are broken down to diols by soluble epoxide hydrolase (sEH), and so inhibiting this enzyme would be expected enhance the beneficial cardiovascular properties of EETs. The rapid development of 1,3-disubstituted urea based sEH inhibitors (sEHIs) has resulted in a number of studies demonstrating cardiovascular protection, and it has been shown that sEHIs are anti-hypertensive, anti-inflammatory, and protect the brain, heart and kidney from damage. Although challenges for the future exist — including improving the drug like properties of sEHIs and finding better ways to target sEHIs to specific tissues — the recent initiation of first in human clinical trials has highlighted the promise of sEHIs as a therapeutic target.
PMCID: PMC3021468  PMID: 19794443
25.  Development of Epoxyeicosatrienoic Acid Analogs with in Vivo Anti-Hypertensive Actions 
Epoxyeicosatrienoic acids (EETs) contribute importantly to the regulation of vascular tone and blood pressure control. The purpose of this study was to develop stable EET analogs and test their in vivo blood pressure lowering effects in hypertensive rats. Using the pharmacophoric moiety of EETs, ether EET analogs were designed with improved solubility and resistance to auto-oxidation and metabolism by soluble epoxide hydrolase. Ether EET analogs were chosen based on their ability to dilate afferent arterioles and subsequently tested for blood pressure lowering effects in rodent models of hypertension. Initially, 11,12-ether-EET-8-ZE failed to lower blood pressure in angiotensin hypertension or spontaneously hypertensive rats (SHR). Esterification of the carboxylic group of 11,12-ether-EET-8-ZE prevented blood pressure increase in SHR when injected at 2 mg/day for 12 days (MAP Δ change at day 8 of injection was −0.3 ± 2 for treated and 12 ± 1 mmHg for control SHR). Amidation of the carboxylic group with aspartic acid produced another EET analog (NUDSA) with a blood pressure lowering effect when injected at 3 mg/day in SHR for 5 days. Amidation of the carboxylic group with lysine amino acid produced another analog with minimal blood pressure lowering effect. These data suggest that esterification of the carboxylic group of 11,12-ether-EET-8-ZE produced the most effective ether-EET analog in lowering blood pressure in SHR and provide the first evidence to support the use of EET analogs in treatment of cardiovascular diseases.
PMCID: PMC3059925  PMID: 21423396
hypertension; blood pressure; afferent arteriole; epoxyeicosanoids; vasodilation

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