20-HETE and the kidney: resolution of old problems and new beginnings

McGiff, John C.; Quilley, John

doi:10.1152/ajpregu.1999.277.3.r607

Cited by 129 publications

(236 citation statements)

References 78 publications

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“…It has been shown that both COX and cytochrome P-450 monooxygenase are expressed in the mTAL (6,9,20,24). Therefore, we explored the possibility that the effect of AA was mediated by either COX-dependent or cytochrome P-450-dependent metabolites of AA.…”

Section: Resultsmentioning

confidence: 99%

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Arachidonic acid inhibits K channels in basolateral membrane of the thick ascending limb

Wang

2002

American Journal of Physiology-Renal Physiology

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We have used the patch-clamp technique to study the effect of arachidonic acid (AA) on the basolateral K channels in the medullary thick ascending limb (mTAL) of rat kidney. An inwardly rectifying 50-pS K channel was identified in cell-attached and inside-out patches in the basolateral membrane of the mTAL. The channel open probability (Po) was 0.51 at the spontaneous cell membrane potential and decreased to 0.25 by 30 mV hyperpolarization. The addition of 5 M AA decreased channel activity, identified as NPo, from 0.58 to 0.08 in cell-attached patches. The effect of AA on the 50-pS K channel was specific because 10 M cis-11,14,17-eicosatrienoic acid had no significant effect on channel activity. To determine whether the effect of AA was mediated by AA per se or by its metabolites, we examined the effect of AA on channel activity in the presence of indomethacin, an inhibitor of cyclooxygenase, or N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), an inhibitor of cytochrome P-450 monooxygenase. Inhibition of cyclooxygenase increased channel activity from 0.54 to 0.9. However, indomethacin did not abolish the inhibitory effect of AA on the 50-pS K channel. In contrast, inhibition of cytochrome P-450 metabolism not only increased channel activity from 0.49 to 0.83 but also completely abolished the effect of AA. Moreover, addition of DDMS can reverse the inhibitory effect of AA on channel activity. The notion that the effect of AA was mediated by cytochrome P-450-dependent metabolites of AA is also supported by the observation that addition of 100 nM of 20-hydroxyeicosatetraenoic acid, a main metabolite of AA in the mTAL, can mimic the effect of AA. We conclude that AA inhibits the 50-pS K channel in the basolateral membrane of the mTAL and that the effect of AA is mainly mediated by cytochrome P-450-dependent metabolites of AA.cyclooxygenase; cytochrome P-450 -oxidation; 20-hydroxyeicosatetraenoic acid; basolateral K channel K CHANNELS IN THE BASOLATERAL membrane of the medullary thick ascending limb (mTAL) play an important role in the regulation of epithelial transport in the loop of Henle. The basolateral K channels in the mTAL are responsible for K recycling across the basolateral membrane and participate in generating the cell membrane potential (Fig.

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Section: Resultsmentioning

confidence: 99%

“…Eicosanoids have been demonstrated to regulate the transepithelial NaCl transport in the mTAL (1,2,13,15,20). Moreover, a large body of evidence indicates that cytochrome P-450-dependent metabolites of arachidonic acid (AA) play an important role in regulating a variety of ion transporters in the kidney (8,23,27,29).…”

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confidence: 99%

Arachidonic acid inhibits K channels in basolateral membrane of the thick ascending limb

Wang

2002

American Journal of Physiology-Renal Physiology

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“…20-HETE production in the kidney may increase blood pressure in rats through at least three mechanisms: i) 20-HETE might constrict the renal artery through inhibition Ca 2+ -activated K + channels in smooth muscle directly, ii) 20-HETE also acts indirectly as a second messenger for ET-1 and iii) it serves as mediator of selective renal effects of angiotensin II [1,[33][34][35][36]. This is supported by the discovery in the unx/salt/DOCA model, which rats that were uni-nephrectonized, given excess salt and treated with DOCA, had increased blood pressure, which increased progressively over the 3-wk study.…”

Section: Discussionmentioning

confidence: 99%

Long-term modifications of blood pressure in normotensive and spontaneously hypertensive rats by gene delivery of rAAV-mediated cytochrome P450 arachidonic acid hydroxylase

et al. 2005

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Arachidonic acid cytochrome P-450 (CYP) hydroxylase 4A isoforms, including 4A1, 4A2, 4A3 and 4A8 in the rat kidney, catalyze arachidonic acid to produce 19/20-Hydroxyeicosatetraenoic acids (20-HETE), a biologically active metabolite, which plays an important role in the regulation of blood pressure. However, controversial results have been reported regarding the exact role of 20-HETE on blood pressure. In the present study, we used recombinant adenoassociated viral vector (rAAV) to deliver CYP 4A1 cDNA and antisense 4A1 cDNA into Sprague-Dawley (SD) rats and spontaneously hypertensive rats (SHR), respectively, to investigate the effects of long-term modifications of blood pressure and the potential for gene therapy of hypertension. The mean systolic pressure increased by 14.2±2.5 mm Hg in rAAV·4A1-treated SD rats and decreased by 13.7±2.2 mm Hg in rAAV·anti4A1-treated SHR rats 5 weeks after the injection compared with controls and these changes in blood pressure were maintained until the experiments ended at 24 weeks. In 4A1 treated animals CYP4A was overexpressed in various tissues, but preferentially in the kidney at both mRNA and protein levels. In anti-4A1-treated SHR, CYP4A mRNA in various tissues was probed, especially in kidneys, but 4A1 protein expression was almost completely inhibited. These results suggest that arachidonic acid CYP hydroxylases contribute not only to the maintenance of normal blood pressure but also to the development of hypertension. rAAV-mediated anti4A administration strategy has the potential to be used as targeted gene therapy in human hypertension by blocking expression of CYP 4A in kidneys.

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“…In contrast to ABT-treated LE rats, urine flow and free C H2O increased significantly, and urine osmolality fell in BB rats. The diuretic response seen in BB was unexpected, because EETs and 20-HETE are generally thought to inhibit rather than increase tubular reabsorption of sodium and water in the kidney (26,40).…”

Section: Discussionmentioning

confidence: 99%

“…These compounds have been reported to play an important role in the control of both renal tubular and vascular function (26). EETs are potent endothelial-derived vasodilators in the renal circulation (17,47).…”

mentioning

confidence: 99%

CytochromeP-450-dependent metabolism of arachidonic acid in the kidney of rats with diabetes insipidus

Sarkis¹,

Ito²,

Mori³

et al. 2005

American Journal of Physiology-Renal Physiology

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. Cytochrome P-450-dependent metabolism of arachidonic acid in the kidney of rats with diabetes insipidus. Am J Physiol Renal Physiol 289: F1333-F1340, 2005. First published July 12, 2005 doi:10.1152/ajprenal.00188.2005.-This study compared the renal metabolism of arachidonic acid in Brattleboro (BB) (vasopressin deficient) and Long-Evans (LE) control rats and the effects of a cytochrome P-450 (CYP) inhibitor 1-aminobenzotriazole (ABT) on renal function in these animals. The production of 20-hydroxyeicosatetraenoic acid (20-HETE) by renal cortical and outer medullary microsomes was significantly greater in BB than in LE rats (155 Ϯ 16 vs. 92 Ϯ 13 and 59 Ϯ 7 vs. 33 Ϯ 3 pmol ⅐ min Ϫ1 ⅐ mg protein Ϫ1 ). Renal cortical epoxygenase activity was not different in these strains. The expression of CYP4A proteins was 58 and 78% higher in the renal cortex and outer medulla of BB than in LE rats. Chronic treatment of BB rats with a vasopressin type 2 receptor agonist for 1 wk normalized the renal production of 20-HETE. Chronic blockade of the formation of 20-HETE and EETs with ABT had little effect on renal function in LE rats. However, urine flow increased by 54% and urine osmolarity decreased by 33% in BB rats treated with ABT. Plasma levels of oxytocin fell significantly from 7.2 Ϯ 1.3 to 3.9 Ϯ 1.0 pg/ml. The effects of ABT in BB rats were attenuated by chronic infusion of oxytocin (0.7 ng ⅐ min Ϫ1 ⅐ 100 g Ϫ1 ) to maintain fixed high plasma levels of this hormone. These results indicate that the expression of CYP4A protein and the renal formation of 20-HETE are elevated in the kidney of BB rats due to a lack of vasopressin and that chronic blockade of the formation of 20-HETE and EETs with ABT promotes water excretion in vasopressin-deficient BB rats by reducing the circulating levels of oxytocin, which is a weak vasopressin agonist. Brattleboro rats; 20-hydroxyeicosatetraenoic acid; cytochrome P-450; epoxyeicosatrienoic acid; renal hemodynamics ARACHIDONIC ACID (AA) is metabolized by cytochrome P-450 (CYP) enzymes in the kidney to produce epoxyeicosatrienoic acids (EETs), 20-hydroxyeicosatetraenoic acid (20-HETE), and dihydroxyeicosatrienoic acids (DiHETEs). These compounds have been reported to play an important role in the control of both renal tubular and vascular function (26). EETs are potent endothelial-derived vasodilators in the renal circulation (17, 47). They also inhibit sodium and water reabsorption in the collecting duct (40). In contrast, 20-HETE is produced by vascular smooth muscle cells and is a potent constrictor of renal arterioles (5,19,23). Inhibition of the synthesis of 20-HETE attenuates the vasoconstrictor response of renal arterioles to elevations in transmural pressure in vitro (16, 18) and autoregulation of renal blood flow and tubuloglomerular feedback responses in vivo (8,48). At the level of the renal tubules, 20-HETE inhibits sodium reabsorption in the proximal tubule and thick ascending limb of the loop of Henle (6,32,34,39).Previous studies indicated that the renal production of EETs an...

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20-HETE and the kidney: resolution of old problems and new beginnings

Cited by 129 publications

References 78 publications

Arachidonic acid inhibits K channels in basolateral membrane of the thick ascending limb

Arachidonic acid inhibits K channels in basolateral membrane of the thick ascending limb

Long-term modifications of blood pressure in normotensive and spontaneously hypertensive rats by gene delivery of rAAV-mediated cytochrome P450 arachidonic acid hydroxylase

CytochromeP-450-dependent metabolism of arachidonic acid in the kidney of rats with diabetes insipidus

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