P450-Dependent Arachidonic Acid Metabolism and Angiotensin II–Induced Renal Damage

Kaergel, Eva; Müller, Dominik N.; Honeck, Horst; Theuer, Juergen; Shagdarsuren, Erdenechimeg; Mullally, Alexander; Luft, Friedrich C.; Schunck, Wolf‐Hagen

doi:10.1161/01.hyp.0000029240.44253.5e

Cited by 60 publications

(44 citation statements)

References 41 publications

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“…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. 21 The current study extends these findings by examining whether angiotensin II infusion leads to persistent salt-sensitive hypertension even after removal of the angiotensin.…”

Section: Discussionmentioning

confidence: 95%

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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Section: Discussionmentioning

confidence: 95%

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

et al. 2003

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“…Lyon hypertensive rats also have a decreased renal epoxygenase activity that contributes to the increase in arterial blood pressure (65,69). Transgenic rats overexpressing both human renin and angiotensinogen genes (dTGR) develop hypertension and renal failure that are associated with decreased kidney epoxygenase enzymatic activity and CYP2C11, CYP2C23, and CYP2J protein levels (53,74,75). Similarly, we have found that an inability to increase renal cortical and vascular CYP2C11 and CYP2C23 protein expression may contribute to salt sensitivity of angiotensin-dependent hypertension (109,110).…”

Section: Renal and Cardiovascular Protective Actions Of Eets And Sehmentioning

confidence: 92%

Epoxide hydrolase and epoxygenase metabolites as therapeutic targets for renal diseases

Imig¹

2005

American Journal of Physiology-Renal Physiology

210

246

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[775][776][777][778][779][780] 2003) have provided compelling evidence that cytochrome P-450-derived EETs have antihypertensive properties and are endothelially derived hyperpolarizing factors (EDHFs) in the kidney. EETs also possess anti-inflammatory actions that could protect the kidney vasculature from injury during renal and cardiovascular diseases. A tactic that has been used to increase EET levels has been inhibition of the soluble epoxide hydrolase enzyme. Epoxide hydrolase inhibitors have been demonstrated to be antihypertensive and renal protective. Thus the renal and cardiovascular protective actions of increasing epoxygenase levels could be translated to therapies for preventing end-organ damage. epoxyeicosatrienoic acids; endothelium-derived hyperpolarizing factor; hypertension; nephropathy; inflammation A MAJOR CAUSE OF MORBIDITY and mortality is the progression of organ damage associated with renal and cardiovascular diseases. For instance, the incidence of end-stage renal disease (ESRD) is escalating and the number of patients on dialysis is predicted to double over the 10-yr period of 2000 -2010 (7, 9, 19, 34, 104). The two main diseases responsible for the increase in ESRD are diabetes and hypertension. One contributing factor to end-organ damage is an impaired endothelium (6,21,56,60,95). Interestingly, endothelial dysfunction has recently been touted as a marker for unfavorable cardiovascular prognosis in humans (5,27,66). Others and we have established that cytochrome P-450 (CYP) metabolites (CYP2C) produced by the endothelium have antihypertensive properties and proposed that the epoxyeicosatrienoic acids (EETs) are endothelium-derived hyperpolarizing factors (EDHFs) (2,12,30,43,50,87). Additionally, EETs have profibrinolytic effects, anti-inflammatory actions, and inhibit smooth vascular muscle cell migration (11,20,32,78,79,94). Recent interest has also focused on the role of soluble epoxide hydrolase (SEH) in renal and cardiovascular disease and inhibition of this enzyme as an avenue to increase EET levels. This review will highlight these favorable EET properties that could protect the kidney from ESRD during renal and cardiovascular disease states. EPOXYGENASE METABOLITES AS AN EDHF AND BEYONDThe contribution of the endothelial cells to the control of blood flow has been recognized for over two decades. Earlier studies established that endothelium-derived factors could act on vascular smooth muscle cells to relax or contract arteries (38,68). The identity of nitric oxide and prostaglandins as the main products of the endothelial cells that relax the vascular smooth muscle has been well established (10,38,67,68). In addition, the fact that the endothelium released one or more substances that relaxed vascular smooth muscle cells through membrane hyperpolarization was also repeatedly demonstrated (10,67,95). A number of studies have provided evidence that this nitric oxide-and cyclooxygenase (COX)-independent endothelium-derived relaxing factor was a metabolite of the arachidonic acid c...

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“…51 However, there are also reports linking salt-induced and angiotensin II-induced hypertension to the failure to increase epoxygenase expression, particularly in the kidney. [52][53][54] Genetic hypertension seems to be differentially linked to CYP expression and activity, because there seems to be no difference in the arachidonic acid-induced generation of EETs by kidneys from SHRs and Wistar-Kyoto rats. 51 Such data imply that alternative mechanisms may underlie the increased renal vasodilator effect of arachidonic acid in the SHR kidney.…”

Section: Eets and Hypertensionmentioning

confidence: 99%

Endothelium-Derived Epoxyeicosatrienoic Acids and Vascular Function

2006

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Abstract-Epoxyeicosatrienoic acids (EETs) are epoxides of arachidonic acid generated by cytochrome P450 (CYP) epoxygenases. The activation of CYP epoxygenases in endothelial cells is an important step in the NO and prostacyclin-independent vasodilatation of several vascular beds, and EETs have been identified as an endotheliumderived hyperpolarizing factor. However, EETs also exert membrane potential-independent effects and modulate several signaling cascades that affect endothelial cell proliferation and angiogenesis. This review summarizes the role of CYP-derived EETs in endothelium-derived hyperpolarizing factor-mediated responses and highlights the evidence indicating that EETs are important second messengers involved in endothelial cell signaling pathways related to angiogenesis. (Hypertension. 2006;47:629-633.)Key Words: calcium channels Ⅲ endothelium-derived factors Ⅲ hypertension Ⅲ vasodilatation T here is now considerable evidence linking the metabolism of arachidonic acid by cytochrome P450 (CYP) enzymes with the regulation of vascular homeostasis and tone, as well as renal function. The enzymes in question fall into 2 classes: (1) the epoxygenases, which generate epoxyeicosatrienoic acids (EETs); and (2) the /-1 hydroxylases, which generate 20-hydroxyeicosatetraenoic acid (20-HETE). EETs and Endothelium-Derived Hyperpolarizing FactorInterest in the vascular actions of EETs was initially related to their identification as an endothelium-derived hyperpolarizing factor (EDHF), that is, compounds responsible for the NO and prostacyclin-independent but endothelium-dependent vasodilatation of some vascular beds. There is now convincing evidence indicating that the hyperpolarizing factor produced by coronary and renal arteries from several species (humans, pigs, cows, dogs, rats, and rabbits) displays characteristics similar to those of a cytochrome CYP-derived metabolite of arachidonic acid. 1 A CYP-dependent, EDHF response has also been described in other human arteries/vascular beds including the mammary artery, 2 the forearm vasculature, 3 and thigh skeletal muscle circulation. 4 However, the EDHFmediated relaxations in human mesenteric arteries 5 and renal arteries 6 appear to be independent of CYP activity. For those following the "EDHF story," the literature has been highly confusing, and for several years the field seemed caught in a pantomime of "it is" versus "it isn't" reports. One reason for the confusion was that although some EDHFmediated responses could be attributed to a CYP-derived metabolite of arachidonic acid, there were clearly other responses that occurred entirely independently of the activation of a CYP enzyme. For comprehensive reviews on the nature of the different EDHFs, the reader should consult references. [7][8][9] Part of the reason for some of the controversy was that EETs were initially reported to initiate smooth muscle hyperpolarization by activating iberiotoxin-sensitive large conductance Ca 2ϩ -activated K ϩ (BK Ca ) channels, 10 whereas EDHFdependent relaxation was mor...

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P450-Dependent Arachidonic Acid Metabolism and Angiotensin II–Induced Renal Damage

Cited by 60 publications

References 41 publications

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

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

Epoxide hydrolase and epoxygenase metabolites as therapeutic targets for renal diseases

Endothelium-Derived Epoxyeicosatrienoic Acids and Vascular Function

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