The kidney cytochrome P-450 2C23 arachidonic acid epoxygenase is upregulated during dietary salt loading

Holla, Vijaykumar; Makita, Keiko; Zaphiropoulos, Peter G.; Capdevila, Jorge H.

doi:10.1172/jci7013

Cited by 118 publications

(156 citation statements)

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“…11,15 CYP2C isoforms are considered the major renal arachidonic acid epoxygenases in the kidney. In particular, CYP2C23 is highly expressed in rat kidney, where it exerts an important role in regulating EET formation.…”

Section: Discussionmentioning

confidence: 99%

“…Three CYP2C subfamily isoforms (CYP2C23, CYP2C24, and CYP2C11) are expressed in the rat kidney, with CYP2C23 being the predominate. 11 Recent studies showed that CYP2J protein is expressed in rat kidney, and CYP2J protein expression is increased in spontaneously hypertensive rats. 12,13 The main product of CYP2C23 isoform is 11,12-EET (57% of the products), although CYP2C11 epoxidizes the 11,12-olefins and 14,15-olefins with nearly equal efficiency.…”

mentioning

confidence: 99%

“…14 Salt sensitivity is the causative agent for an important subgroup of humans with essential hypertension. 11 Considerable evidence suggests that endothelial dysfunction is linked to end-organ damage in human salt-sensitive hypertension. Studies have revealed that renal CYP450 -hydroxylase and epoxygenase activity are differentially modified by sodium chloride.…”

mentioning

confidence: 99%

“…15,16 In contrast, the expression of CYP2C11 and CYP2C23 and the formation of EETs in the kidney are increased by a high-salt diet. 11,15 Although studies in Sprague-Dawley rats suggest that a salt-inducible renal epoxygenase has antihypertensive properties, kidney EET production is inappropriately low during the development of salt-sensitive hypertension. 17 There are many CYP450 isoforms, expressed in the kidney, that produce EETs; however, little is known about which of these isoforms are regulated in the renal microvessels and about their involvement in the development of angiotensin salt-sensitive hypertension.…”

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confidence: 99%

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

et al. 2003

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Abstract-Excess dietary salt intake differentially modulates the activity of cytochrome (CYP) P450 enzymes in kidney cortex. Exactly how increased angiotensin (Ang) II levels and hypertension change the regulatory effect of high salt on CYP450 enzymes remains unclear. The present study investigated the effects of combined administration of Ang II and a high-salt diet on P450 epoxygenase and hydroxylase protein levels in kidney, as well as afferent arteriolar responses to acetylcholine and sodium nitroprusside. High dietary salt administration for 14 days resulted in increased renal cortical CYP2C11 protein levels, and a significant increase of CYP2C11 and CYP2C23 protein levels in renal microvessels. Administration of Ang II in combination with a high-salt diet prevented the upregulation of renal cortical CYP2C11 protein expression observed with high dietary salt alone, and significantly downregulated expression of CYP2C11, CYP2C23, and CYP2J protein in renal microvessels. A high-salt diet alone decreased CYP4A protein in kidney cortex, and renal cortical CYP4A protein level remained at a low level in Ang II-infused rats treated with a high-salt diet. Increases in blood pressure during Ang II infusion were greater in rats fed a high-salt diet. In addition, afferent arteriolar responsiveness to acetylcholine and sodium nitroprusside was significantly attenuated in Ang II-treated rats versus controls. This decrease was significantly enhanced in Ang II-treated rats given a high-salt diet. These results support the hypothesis that an inability to upregulate CYP2C and maintain CYP2J in the rat kidney and impaired afferent arteriolar vasodilation with chronic Ang II infusion contribute to salt-induced elevation of arterial pressure.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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

et al. 2003

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“…The P450 arachidonic acid epoxygenases catalyze the metabolism of endogenous pools of arachidonic acid to 5,6-, 8,9-, 11,12-, and 14,15-EET (12)(13)(14)(15)(16)(17), a reaction catalyzed predominantly by members of the P450 CYP2C gene subfamily (12). Furthermore, CYP2C8, CYP2C23, and Cyp2c44 have been identified as predominant stereoselective epoxygenases in several human, rat, and mouse organ tissues (12,13,17,18).…”

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confidence: 99%

Characterization of 5,6- and 8,9-Epoxyeicosatrienoic Acids (5,6- and 8,9-EET) as Potent in Vivo Angiogenic Lipids

Pozzi¹,

Macias‐Perez²,

Abair³

et al. 2005

Journal of Biological Chemistry

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The cytochrome P450 arachidonic acid epoxygenase metabolites, the epoxyeicosatrienoic acids (EETs) are powerful, nonregioselective, stimulators of cell proliferation. In this study we compared the ability of the four EETs (5,6-, 8,9-, 11,12-, and 14,15-EETs) to regulate endothelial cell proliferation in vitro and angiogenesis in vivo and determined the molecular mechanism by which EETs control these events. Inhibition of the epoxygenase blocked serum-induced endothelial cell proliferation, and exogenously added EETs rescued cell proliferation from epoxygenase inhibition. Studies with selective ERK, p38 MAPK, or PI3K inhibitors revealed that whereas activation of p38 MAPK is required for the proliferative responses to 8,9-and 11,12-EET, activation of PI3K is necessary for the cell proliferation induced by 5,6-and 14,15-EET. Among the four EETs, only 5,6-and 8,9-EET are capable of promoting endothelial cell migration and the formation of capillary-like structures, events that are dependent on EET-mediated activation of ERK and PI3K. Using subcutaneous sponge models, we showed that 5,6-and 8,9-EET are pro-angiogenic in mice and that their neo-vascularization effects are enhanced by the co-administration of an inhibitor of EET enzymatic hydration, presumably because of reduced EET metabolism and inactivation. These studies identify 5,6-and 8,9-EET as powerful and selective angiogenic lipids, provide a functional link between the EET proliferative chemotactic properties and their angiogenic activity, and suggest a physiological role for them in angiogenesis and de novo vascularization.

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Distal Convoluted Tubule

McCormick

Ellison

2014

Comprehensive Physiology

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The distal convoluted tubule (DCT) is a short nephron segment, interposed between the macula densa and collecting duct. Even though it is short, it plays a key role in regulating extracellular fluid volume and electrolyte homeostasis. DCT cells are rich in mitochondria, and possess the highest density of Na + /K + -ATPase along the nephron, where it is expressed on the highly amplified basolateral membranes. DCT cells are largely water impermeable, and reabsorb sodium and chloride across the apical membrane via electroneurtral pathways. Prominent among this is the thiazide-sensitive sodium chloride cotransporter, target of widely used diuretic drugs. These cells also play a key role in magnesium reabsorption, which occurs predominantly, via a transient receptor potential channel (TRPM6). Human genetic diseases in which DCT function is perturbed have provided critical insights into the physiological role of the DCT, and how transport is regulated. These include Familial Hyperkalemic Hypertension, the salt-wasting diseases Gitelman syndrome and EAST syndrome, and hereditary hypomagnesemias. The DCT is also established as an important target for the hormones angiotensin II and aldosterone; it also appears to respond to sympathetic-nerve stimulation and changes in plasma potassium. Here, we discuss what is currently known about DCT physiology. Early studies that determined transport rates of ions by the DCT are described, as are the channels and transporters expressed along the DCT with the advent of molecular cloning. Regulation of expression and activity of these channels and transporters is also described; particular emphasis is placed on the contribution of genetic forms of DCT dysregulation to our understanding.

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The kidney cytochrome P-450 2C23 arachidonic acid epoxygenase is upregulated during dietary salt loading

Cited by 118 publications

References 42 publications

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

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

Characterization of 5,6- and 8,9-Epoxyeicosatrienoic Acids (5,6- and 8,9-EET) as Potent in Vivo Angiogenic Lipids

Distal Convoluted Tubule

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