Decreased Renal Cytochrome P450 2C Enzymes and Impaired Vasodilation Are Associated With Angiotensin Salt-Sensitive Hypertension

Zhao, Xueying; Pollock, David M.; Inscho, Edward W.; Zeldin, Darryl C.; Imig, John D.

doi:10.1161/01.hyp.0000047877.36743.fa

Cited by 104 publications

(132 citation statements)

References 42 publications

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“…3,4,38 Salt-sensitive hypertension has also been linked to an inability of the kidney to increase EET generation. 10,39 We provided additional evidence in this study that increasing epoxide-diol ratios ameliorated the renal injury associated with angiotensin salt-sensitive hypertension. We cannot separate the direct effects of increasing EET levels versus blood pressure effects on kidney damage because blood pressure decreased in angiotensin hypertensive animals treated with AUDA.…”

Section: Imig Et Al Epoxides and Angiotensin Hypertension 979mentioning

confidence: 56%

An Orally Active Epoxide Hydrolase Inhibitor Lowers Blood Pressure and Provides Renal Protection in Salt-Sensitive Hypertension

et al. 2005

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Abstract-The present study tested the hypothesis that increasing epoxyeicosatrienoic acids by inhibition of soluble epoxide hydrolase (sEH) would lower blood pressure and ameliorate renal damage in salt-sensitive hypertension. Rats were infused with angiotensin and fed a normal-salt diet or an 8% NaCl diet for 14 days. The sEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), was given orally to angiotensin-infused animals during the 14-day period. Plasma AUDA metabolite levels were measured, and they averaged 10Ϯ2 ng/mL in normal-salt angiotensin hypertension and 19Ϯ3 ng/mL in high-salt angiotensin hypertension on day 14 in the animals administered the sEH inhibitor. Mean arterial blood pressure averaged 161Ϯ4 mm Hg in normal-salt and 172Ϯ5 mm Hg in the high-salt angiotensin hypertension groups on day 14. EH inhibitor treatment significantly lowered blood pressure to 140Ϯ5 mm Hg in the normal-salt angiotensin hypertension group and to 151Ϯ6 mm Hg in the high-salt angiotensin hypertension group on day 14. The lower arterial blood pressures in the AUDA-treated groups were associated with increased urinary epoxide-to-diol ratios. Urinary microalbumin levels were measured, and ED-1 staining was used to determine renal damage and macrophage infiltration in the groups. Two weeks of AUDA treatment decreased urinary microalbumin excretion in the normal-salt and high-salt angiotensin hypertension groups and macrophage number in the high-salt angiotensin hypertension group. These data demonstrate that sEH inhibition lowers blood pressure and ameliorates renal damage in angiotensin-dependent, salt-sensitive hypertension. Key Words: kidney Ⅲ inflammation Ⅲ endothelium-derived factors Ⅲ albuminuria A lthough treatment of hypertension has significantly advanced in recent decades, a chronic elevation in blood pressure still results in progressive renal damage, as evidenced by the escalating incidence of end-stage renal disease (ESRD). 1,2 The development of hypertension after long-term administration of angiotensin has many of the same renal and vascular changes that are associated with human essential hypertension. 3,4 Likewise, animal models of angiotensindependent hypertension demonstrate a further elevation in blood pressure when fed a high-salt diet or salt sensitivity. [3][4][5] High dietary salt also increases the susceptibility to kidney damage in hypertensive patients and in angiotensindependent hypertensive rats. 3,4 These parallels between patients with essential hypertension and the angiotensin infusion model make this an extremely useful model to evaluate early changes that occur in the kidney that ultimately result in ESRD.Cytochrome P450 epoxygenase metabolites are involved in the long-term regulation of blood pressure and in the response of the kidney to a high-salt diet. 6 -8 Similarly, salt-sensitive hypertension is associated with an inability of the kidney to properly increase epoxygenase levels. 8 -10 Recent studies have provided evidence that increasing epoxygenase levels have renal-and c...

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Section: Imig Et Al Epoxides and Angiotensin Hypertension 979mentioning

confidence: 56%

An Orally Active Epoxide Hydrolase Inhibitor Lowers Blood Pressure and Provides Renal Protection in Salt-Sensitive Hypertension

et al. 2005

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“…21 To determine if an inability to upregulate the CYP2C and CYP2J isoforms was associated with the persistent hypertension after exposure to angiotensin II, we evaluated epoxygenase mRNA and protein expression in renal microvessels. Figure 2 and Figure 3 show representative Western blots and densitometric analysis of CYP2C11, CYP2C23, and CYP2J protein in renal microvessels.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have shown an impaired ability to upregulate renal epoxygenase enzymes in animal models of salt-sensitive hypertension. 20,21 In addition, kidney-specific downregulation of P450 epoxygenase enzymes is associated with hypertension and endorgan damage in transgenic rats overexpressing both human renin and angiotensinogen genes (dTGR). 26 We have previously reported that chronic angiotensin II infusion combined with a high salt diet was associated with decreased CYP2C11, CYP2C23, and CYP2J protein levels in renal vasculature and that this may contribute to the development of salt-sensitive hypertension.…”

Section: Discussionmentioning

confidence: 99%

“…11,18 -20 Our previous study also showed that P450 epoxygenase protein levels were significantly decreased in angiotensin II-infused animals fed a high-salt diet. 21 The purpose of the present study was to determine if an inability to upregulate P450 epoxygenase enzymes is associated with persistent salt-sensitive hypertension after 2 weeks of exposure to angiotensin II. …”

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confidence: 99%

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Salt-Sensitive Hypertension After Exposure to Angiotensin Is Associated With Inability to Upregulate Renal Epoxygenases

et al. 2003

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Abstract-The current study was designed to determine whether angiotensin II infusion could lead to persistent salt-sensitive hypertension and to examine involvement of renal microvascular epoxygenases in this process. Six groups were studied: rats maintained on a normal salt diet for 4 weeks (NS); rats maintained on a high salt diet for 4 weeks (HS); and all other animals receiving angiotensin II (ANG) infusion and being fed a normal or high salt diet for 2 weeks; then the angiotensin II infusion was stopped and diets were either maintained or switched (ANG/NS-NS, ANG/NS-HS, ANG/HS-HS, ANG/HS-NS). Angiotensin II infusion resulted in a rise in blood pressure and an increase in urinary albumin excretion over the 2-week period. After angiotensin II withdrawal, blood pressure returned to normal in animals receiving a normal salt diet from weeks 2 to 4 (ANG/NS-NS and ANG/HS-NS groups). In contrast, blood pressure remained elevated in the group maintained on a high salt diet throughout the entire 4-week period (ANG/HS-HS group).Renal microvascular CYP2C11 and CYP2C23 protein levels were decreased by 50% to 60% in the ANG/HS-HS group compared with the NS group. Likewise, renal microvascular CYP2J protein was significantly decreased in the ANG/HS-HS group versus the NS group. Renal microvascular CYP2C11 and CYP2C23 mRNA levels were reduced in the ANG/HS-HS group compared with both the NS and HS groups. These results support the hypothesis that angiotensin II infusion induces persistent salt-sensitive hypertension after withdrawal of angiotensin II that may be due to downregulation of CYP2C and CYP2J epoxygenases in renal microvessels. Key Words: endothelium-derived factors Ⅲ hypertension, sodium-dependent Ⅲ angiotensin II Ⅲ kidney Ⅲ vessels E poxygenase metabolites, the epoxyeicosatrienoic acids (EETs), contribute to integrated kidney function by directly affecting tubular transport processes, vascular tone, and cellular proliferation. [1][2][3][4][5][6] EETs are generally considered to be antihypertensive as the result of their vasodilatory and sodium transport properties. 2,3,7-9 Epoxidation of arachidonic acid has been attributed to members of the CYP2C and CYP2J subfamilies. 10 -13 CYP2C subfamily isoforms are abundantly expressed in rat kidney, with CYP2C23 being the predominant isoform. 11 Recent studies have shown that CYP2J protein is also expressed in rat kidney and that CYP2J protein expression is increased in spontaneously hypertensive rats. 13 Salt sensitivity is an important characteristic of a subgroup of humans with essential hypertension and other forms of salt-dependent hypertension that occurs in blacks, diabetics, patients treated with cyclosporine, or with aging. 14,15 Previous studies in animal models of hypertension demonstrate that salt-sensitive hypertension develops after short-term exposure to angiotensin II. 16,17 The mechanisms by which transient angiotensin II-mediated blood pressure elevation can lead to persistent salt-sensitive hypertension have not been completely elucidated. Studies in ...

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“…IL-6 has been demonstrated to downregulate CYP epoxygenase enzymes [91,92]. There are increased IL-6 levels and an inability to increase renal CYP epoxygenase expression in angiotensin salt-sensitive hypertension [33,93]. A recent study utilizing IL-6 gene deficient mice has demonstrated protection from renal damage in hypertension and that the decrease in injury was associated with an increased CYP expoxygenase expression [33].…”

Section: Emerging Therapeutic Approaches For Epoxyeicosanoids and Renmentioning

confidence: 99%

Eicosanoids and renal damage in cardiometabolic syndrome

Imig

2008

Expert Opinion on Drug Metabolism & Toxicology

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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. Keywordskidney; epoxyeicosatrienoic acids; epoxide hydrolase; obesity; cytokines; inflammation Cardiometabolic SyndromeIn recent years, the number of obese people in the world is growing rapidly and has reached epidemic status. Obesity is the central phenotype in metabolic syndrome, also known as cardiometabolic syndrome that clusters with other cardiovascular risk factors. These other cardiovascular risk factors include hypertension, type 2 diabetes, insulin resistance, low high-density lipoproteins (HDL) cholesterol, elevated triglycerides, microalbuminuria, and atherosclerosis [1,2,3] (Figure 1). The Adult treatment Panel II of the National Cholesterol Education Program has defined metabolic syndrome as any three of the following five traits: visceral obesity, hypertension, hypertriglyceridemia, low HDL cholesterol, and impaired fasting glucose [4]. Although obesity is the phenotypic hallmark of cardiometabolic syndrome, the other risk factors that manifest in individuals varies greatly. Blood pressure elevation in obese individuals is closely related to weight gain; however, not all obese individuals become hypertensive [5][6][7][8]. The relationship between obesity and hypertension is well established but the exact consequences to end organ damage remains unknown. Interestingly, hypertension and diabetes account for seventy percent of patients with end stage renal disease (ESRD) and the number of patients with ESRD will double in this decade [9,10]. One of the main reasons for the doubling in ESRD patients is the increase in obesity related type 2 diabetes and its co-existence with hypertension.

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Decreased Renal Cytochrome P450 2C Enzymes and Impaired Vasodilation Are Associated With Angiotensin Salt-Sensitive Hypertension

Cited by 104 publications

References 42 publications

An Orally Active Epoxide Hydrolase Inhibitor Lowers Blood Pressure and Provides Renal Protection in Salt-Sensitive Hypertension

An Orally Active Epoxide Hydrolase Inhibitor Lowers Blood Pressure and Provides Renal Protection in Salt-Sensitive Hypertension

Salt-Sensitive Hypertension After Exposure to Angiotensin Is Associated With Inability to Upregulate Renal Epoxygenases

Eicosanoids and renal damage in cardiometabolic syndrome

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