Inhibitors of 20-HETE Formation Promote Salt-Sensitive Hypertension in Rats

Hoagland, Kimberly M.; Flasch, Averia K.; Roman, Richard J.

doi:10.1161/01.hyp.0000084634.97353.1a

Cited by 79 publications

(70 citation statements)

References 42 publications

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“…Previous studies have demonstrated that the induction of the renal CYP4A enzyme attenuates the development of hypertension in Dahl salt-sensitive rats 15,16,21 and that the inhibition of 20-HETE, a metabolite of CYP4A, causes hypertension. 19,27 Additionally, the antihypertensive actions of 20-HETE can be attributed to inhibition of sodium transport by the proximal tubule and thick ascending limb of the loop of Henle. 14,20,22 Blockade of ion transport in freshly isolated proximal tubules by ET-1 is attenuated by inhibiting 20-HETE synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, 20-HETE has actions to reduce sodium transport and, like ET B receptor activation, has been implicated in saltdependent hypertension. [17][18][19][20][21] Previous studies have provided evidence that 20-HETE contributes to ET-1-mediated natriuretic responses. 22 Blockade of CYP4A and 20-HETE prevented the increase in urinary sodium excretion produced by ET-1.…”

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confidence: 99%

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Peroxisome Proliferator-Activated Receptor-α Activation Reduces Salt-Dependent Hypertension During Chronic Endothelin B Receptor Blockade

et al. 2005

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Abstract-Endothelin B (ET B ) receptor stimulation inhibits sodium transport in a similar fashion as 20-HETE. Clofibrate, a peroxisome proliferator-activated receptor-␣ (PPAR-␣) agonist, increases protein expression of cytochrome P450 4A (CYP4A), which is responsible for 20-HETE synthesis in the kidney. Experiments were designed to determine whether clofibrate reduces hypertension associated with chronic ET B receptor blockade. Male Sprague-Dawley rats received either normal-salt (0.8% NaCl) or high-salt (8% NaCl) diet for 10 days. Female rats were fed a high-salt (8% NaCl) diet for 10 days. During the last 7 days, rats of both sexes were divided into 3 treatment groups: (1) [1][2][3] In the kidney, ET-1 is synthesized from a variety of cells such as vascular endothelium, mesangial cells, tubular epithelial cells, and medullary interstitium. 4 -10 The primary receptor subtype on renal tubular epithelial cells is the ET B receptor. 3 Studies have demonstrated that ET-1 stimulates sodium and water excretion through ET B receptor activation. 11 Consistent with a pronatriuretic function, our laboratory has shown that blocking ET B receptors causes salt-dependent hypertension along with elevated plasma ET-1 levels. 12,13 The latter effect is thought to be attributable to reduced clearance of ET-1 in the absence of ET B receptor availability.The role of cytochrome P450 (CYP450) hydroxylase metabolites in the maintenance of arterial pressure is complex because of their contrasting hypertensive and antihypertensive properties. 14 Clofibrate, a peroxisome proliferator activated receptor-␣ (PPAR-␣) agonist, has been shown to reduce arterial pressure in Dahl salt-sensitive rats on high salt diet by inducing the genes that code for CYP4504A (CYP4A) enzymes in the renal cortex. 15,16 CYP4A is the enzyme responsible for the synthesis of 20-HETE. Interestingly, 20-HETE has actions to reduce sodium transport and, like ET B receptor activation, has been implicated in saltdependent hypertension. [17][18][19][20][21] Previous studies have provided evidence that 20-HETE contributes to ET-1-mediated natriuretic responses. 22 Blockade of CYP4A and 20-HETE prevented the increase in urinary sodium excretion produced by ET-1. 23 Similarly, inhibition of 20-HETE formation in isolated proximal tubules prevented the blockade of ion transport produced by ET-1, indicating that 20-HETE acts as a second messenger of ET-1 in the proximal tubule. 23 Because the ET-1-mediated diuretic and natriuretic effects are through ET B activation, it is reasonable to presume that ET-1 stimulates 20-HETE formation through ET B receptors. The purpose of the present study was to determine the influence of PPAR-␣ activation and upregulation of CYP4A in the salt-sensitive hypertension produced by chronic ET B receptor blockade.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Peroxisome Proliferator-Activated Receptor-α Activation Reduces Salt-Dependent Hypertension During Chronic Endothelin B Receptor Blockade

et al. 2005

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“…The kidneys were rapidly removed and the renal cortex and outer medulla were collected and homogenized separately in 3 ml of a 10 mM potassium buffer (pH 7.7) containing 250 mM sucrose, 1 mM EDTA, and 0.1 mM phenylmethylsulfonyl fluoride (PMSF). Microsomes were prepared as previously described (14). Briefly, homogenates were centrifuged at 3,000 g for 5 min to remove large tissue fragments, and the supernatants were centrifuged at 9,000 g for 15 min to remove mitochondria and nuclei.…”

Section: Methodsmentioning

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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“…For example, the fawn-hooded rat has a genetic defect in renal autoregulation that results in early onset glomerular hypertension, followed by the accelerated development of renal disease (88). Numerous factors are known to govern renal autoregulation (84), including 20-hydroxyeicosatetraenoic acid (20-HETE) (89,90), and hence genetic alterations in any of these mediators could also lead to an abnormal autoregulatory response and increase the risk for progression in the subject with essential hypertension.…”

Section: Why Does Hypertension Progress In Some Subjects But In Othermentioning

confidence: 99%

Essential Hypertension, Progressive Renal Disease, and Uric Acid

Johnson

Segal

Srinivas

et al. 2005

Journal of the American Society of Nephrology

261

171

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Hypertension and hypertension-associated ESRD are epidemic in society. The mechanisms responsible for renal progression in mild to moderate hypertension and those groups most at risk need to be identified. Historic, epidemiologic, clinical, and experimental studies on the pathogenesis of hypertension and hypertension-associated renal disease are reviewed and an overview/hypothesis for the mechanisms involved in renal progression is presented. There is increasing evidence that hypertension may exist in one of two forms/stages. The first stage, most commonly observed in early or borderline hypertension, is characterized by salt-resistance, normal or only slightly decreased GFR, relatively normal or mild renal arteriolosclerosis, and normal renal autoregulation. This group is at minimal risk for renal progression. The second stage, characterized by salt-sensitivity, renal arteriolar disease, and blunted renal autoregulation, defines a group at highest risk for the development of microalbuminuria, albuminuria, and progressive renal disease. This second stage is more likely to be observed in blacks, in subjects with gout or hyperuricemia, with low level lead intoxication, or with severe obesity/metabolic syndrome. The two major mechanistic pathways for causing impaired autoregulation at mild to moderate elevations in BP appear to be hyperuricemia and/or low nephron number. Understanding the pathogenetic pathways mediating renal progression in hypertensive subjects should help identify those subjects at highest risk and may provide insights into new therapeutic maneuvers to slow or prevent progression.

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Inhibitors of 20-HETE Formation Promote Salt-Sensitive Hypertension in Rats

Cited by 79 publications

References 42 publications

Peroxisome Proliferator-Activated Receptor-α Activation Reduces Salt-Dependent Hypertension During Chronic Endothelin B Receptor Blockade

Peroxisome Proliferator-Activated Receptor-α Activation Reduces Salt-Dependent Hypertension During Chronic Endothelin B Receptor Blockade

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

Essential Hypertension, Progressive Renal Disease, and Uric Acid

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