Endothelial-specific CYP4A2 overexpression leads to renal injury and hypertension via increased production of 20-HETE

Inoue, Ken‐ichiro; Sodhi, Komal; Puri, Nitin; Gotlinger, Katherine; Cao, Jiang; Rezzani, Rita; Falck, John R.; Abraham, Nader G.; Laniado−Schwartzman, Michal

doi:10.1152/ajprenal.00364.2009

Cited by 55 publications

(60 citation statements)

References 57 publications

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“…20-HETE is a CYP-derived eicosanoid whose synthesis and actions have been linked to the pathogenesis of hypertension in experimental models and humans (38,42). Numerous reports have demonstrated that the vascular synthesis of 20-HETE increases in experimental models of hypertension; vascular overexpression of CYP4A2-20-HETE synthase leads to hypertension, and inhibition of 20-HETE synthesis results in lower blood pressure (11,28,29,34). 20-HETE exerts powerful biological activities in the vasculature; it constricts smooth muscles, stimulates smooth muscle proliferation and migration, inhibits endothelial nitric oxide synthase, and activates the NF-kB-mediated inflammatory program in the vascular endothelium (3,13,17).…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms by which 20-HETE contributes to vascular remodeling are unclear; however, 20-HETE has been implicated in many of the biochemical changes preceding remodeling of the arterial wall. 20-HETE has been shown to contribute to collagen accumulation in kidneys from hypertensive rats overexpressing CYP4A2 protein (11). It has also been shown to exert proinflammatory actions.…”

Section: Discussionmentioning

confidence: 99%

“…Rat renal interlobar arteries and mouse PGMVs were incubated in oxygenated Krebs biocarbonate buffer (pH 7.4) with 1 mM NADPH for 1 h at 37°C with gentle shaking. 20-HETE was extracted and quantified by liquid chromotographytandem mass spectroscopy (Applied Biosystems, Foster City, CA) as previously described (11). Measurements of media thickness, M/L, and medial cross-sectional area.…”

Section: Methodsmentioning

confidence: 99%

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20-HETE induces remodeling of renal resistance arteries independent of blood pressure elevation in hypertension

Ding

García

et al. 2013

American Journal of Physiology-Renal Physiology

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-Hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P-450 (Cyp)-derived arachidonic acid metabolite that has been shown to increase smooth muscle contractions and proliferation, stimulate endothelial dysfunction and activation, and promote hypertension. We examined if 20-HETE contributes to microvascular remodeling in hypertension. In Sprague-Dawley rats, administration of the 20-HETE biosynthesis inhibitor HET0016 or the ,15(Z)-dienoic acid (20-HEDE) prevented 5␣-dihydrotestosterone (DHT)-induced increases in blood pressure as well as abrogated DHT-induced increases in the media-to-lumen ratio (M/L), media thickness, and collagen IV deposition in renal interlobar arteries. Reserpine prevented blood pressure elevation in DHT-treated rats but did not affect microvascular remodeling (M/L, media thickness, and collagen deposition); under these conditions, treatment with the 20-HETE antagonist attenuated microvascular remodeling, suggesting that 20-HETE contributes to DHT-induced vascular remodeling independent of blood pressure elevation. In Cyp4a14 Ϫ/Ϫ mice, which display androgen-driven and 20-HETE-dependent hypertension, treatment with the 20-HETE antagonist abolished remodeling of renal resistance arteries measured as media thickness (24 Ϯ 1 vs. 15 Ϯ 1 m) and M/L (0.29 Ϯ 0.03 vs. 0.17 Ϯ 0.01). Moreover, in Cyp4a12 transgenic mice in which the expression of Cyp4a12-20-HETE synthase is driven by a tetracycline-sensitive promoter, treatment with doxycycline resulted in blood pressure elevation (140 Ϯ 4 vs. 92 Ϯ 5 mmHg) and a significant increase in remodeling of renal resistance arteries (media thickness: 23 Ϯ 1 vs. 16 Ϯ 1 m; M/L: 0.39 Ϯ 0.04 vs. 0.23 Ϯ 0.02); these increases were abrogated by cotreatment with 20-HEDE. This study demonstrated that 20-HETE is a key regulator of microvascular remodeling in hypertension; its effect is independent of blood pressure elevation and androgen levels. 20-hydroxyeicosatetraenoic acid; cytochrome P-450 4A; blood pressure; androgen VASCULAR REMODELING of large and small arteries contributes to the development and complications of hypertension (25). This process renders arteries stiffer and thicker, leading to detrimental effects on blood pressure regulation (14). Structural alterations of the microcirculation, of which the media-to-lumen ratio (M/L) is the most important predictor, are likely to occur in renal microvessels, as previously shown in experimental models of hypertension (7), including spontaneously hypertensive rats (SHRs), DOCA-salt rats, and one-kidney, one-clip Goldblatt hypertensive rats (12). The mechanisms that contribute to arterial remodeling in hypertension are numerous and include stimulation of growth and apoptosis and increased inflammation and fibrosis. Numerous autacoids have been implicated as mediators of arterial remodeling in hypertension. The most prominent is ANG II, which has been shown to exert the capacity of stimulating vasoconstriction, smooth muscle growth, production of inflammatory cytokines and chemokines, and activating extracellul...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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20-HETE induces remodeling of renal resistance arteries independent of blood pressure elevation in hypertension

Ding

García

et al. 2013

American Journal of Physiology-Renal Physiology

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“…Native CYP4F2 is predominantly expressed in the kidney and liver, and has high ω-hydroxylation activity to catalyze arachidonic acid to 20-HETE (1-3). 20-HETE promotes hypertension by vasoconstriction (4,5) and attenuates hypertension by the inhibition of ion reabsorption (6,7). The dual effect on regulation of blood pressure is spotlighted in the pathophysiology of hypertension.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have demonstrated that 20-HETE has two contradictory effects in the development of hypertension (2,3). One is prohypertension resulting from constriction of the small arteries (4,5). The other is anti-hypertension caused by inhibition of sodium reabsorption (6,7).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of CMV and KAP promoters for driving the expression of human CYP4F2 in transgenic mice

Lai

Liu²,

Wu³

et al. 2011

Int J Mol Med

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Abstract. A transgenic mouse model in which cytochrome P450 4F2 (CYP4F2) was expressed in multiple organs was expected to clarify the role of 20-hydroxyeicosatetraenoic acid (20-HETE) in the regulation of blood pressure, compared with our previously established kidney androgen-regulated protein (KAP) promoter CYP4F2 transgenic mouse model which predominantly showed renal overexpression of CYP4F2. A novel CYP4F2 transgenic mouse model driven by the cyto megalovirus (CMV) promoter was generated and identified by PCR and subsequent sequencing. Extensive study of CMV-CYP4F2 transgenic mice demonstrated that CYP4F2 was exclusively expressed in the liver, while 20-HETE levels in the urine, kidney and blood were not affected, and there was no resulting change in the systolic blood pressure. This was in contrast to KAP-CYP4F2 transgenic mice which exerted prohypertensive action of 20-HETE resulting from the renal overexpression of CYP4F2. In addition, CYP4F2 overwhelmed the endogenous renal Cyp4a family mRNA levels in the KAP-CYP4F2 but not in the CMV-CYP4F2 transgenic mice. These results support the idea that overexpression of renal CYP4F2, leading to high 20-HETE in the urine and blood, may account for the elevated blood pressure. The CMV promoter did not direct CYP4F2 expression into extensive tissues and organs in an attempt to clarify the action of 20-HETE.

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Cytochrome P450 and Lipoxygenase Metabolites on Renal Function

Imig

Khan

2015

Comprehensive Physiology

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Arachidonic acid metabolites have a myriad of biological actions including effects on the kidney to alter renal hemodynamics and tubular transport processes. Cyclooxygenase metabolites are products of an arachidonic acid enzymatic pathway that has been extensively studied in regards to renal function. Two lesser-known enzymatic pathways of arachidonic acid metabolism are the lipoxygenase (LO) and cytochrome P450 (CYP) pathways. The importance of LO and CYP metabolites to renal hemodynamics and tubular transport processes is now being recognized. LO and CYP metabolites have actions to alter renal blood flow and glomerular filtration rate. Proximal and distal tubular sodium transport and fluid and electrolyte homeostasis are also significantly influenced by renal CYP and LO levels. Metabolites of the LO and CYP pathways also have renal actions that influence renal inflammation, proliferation, and apoptotic processes at vascular and epithelial cells. These renal LO and CYP pathway actions occur through generation of specific metabolites and cell-signaling mechanisms. Even though the renal physiological importance and actions for LO and CYP metabolites are readily apparent, major gaps remain in our understanding of these lipid mediators to renal function. Future studies will be needed to fill these major gaps regarding LO and CYP metabolites on renal function.

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Endothelial-specific CYP4A2 overexpression leads to renal injury and hypertension via increased production of 20-HETE

Cited by 55 publications

References 57 publications

20-HETE induces remodeling of renal resistance arteries independent of blood pressure elevation in hypertension

20-HETE induces remodeling of renal resistance arteries independent of blood pressure elevation in hypertension

Evaluation of CMV and KAP promoters for driving the expression of human CYP4F2 in transgenic mice

Cytochrome P450 and Lipoxygenase Metabolites on Renal Function

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