20-Hydroxyeicosatetraeonic Acid: A New Target for the Treatment of Hypertension

Williams, Jan Michael; Murphy, Sydney; Burke, Marilyn; Roman, Richard J.

doi:10.1097/fjc.0b013e3181f04b1c

Cited by 157 publications

(189 citation statements)

References 169 publications

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“…[20][21][22] In parallel, we demonstrate that the renal content of 20-HETE exhibits a clear circadian pattern and that this pattern is significantly modified in kidneys of clock(2/2) mice. 20-HETE has a potent prohypertensive effect by acting as a vasoconstrictor of preglomerular arterioles, but it can also inhibit several important sodium transporters in the proximal tubule and the thick ascending limb (Na + -K + -adenosine triphosphatase, NHE3, NKCC2 Na 1 -K + -Cl 2 cotransporter 2), [23][24][25][26] thereby promoting sodium excretion and lowering BP.…”

Section: Discussionmentioning

confidence: 57%

“…Indeed, drugs targeting the 20-HETE axis present an interesting therapeutic potential for vascular and salt-sensitive hypertension, acute kidney injury, and renal cancer. 22,29,30 Some of these compounds are being tested in preclinical studies. 22 The circadian rhythmicity of 20-HETE levels indicates that the safety and efficiency of these drugs could vary depending on the time they are administered.…”

Section: Discussionmentioning

confidence: 99%

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The Circadian Clock Modulates Renal Sodium Handling

Nikolaeva

Pradervand

Centeno³

et al. 2012

Journal of the American Society of Nephrology

124

122

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The circadian clock contributes to the control of BP, but the underlying mechanisms remain unclear. We analyzed circadian rhythms in kidneys of wild-type mice and mice lacking the circadian transcriptional activator clock gene. Mice deficient in clock exhibited dramatic changes in the circadian rhythm of renal sodium excretion. In parallel, these mice lost the normal circadian rhythm of plasma aldosterone levels. Analysis of renal circadian transcriptomes demonstrated changes in multiple mechanisms involved in maintaining sodium balance. Pathway analysis revealed the strongest effect on the enzymatic system involved in the formation of 20-HETE, a powerful regulator of renal sodium excretion, renal vascular tone, and BP. This correlated with a significant decrease in the renal and urinary content of 20-HETE in clockdeficient mice. In summary, this study demonstrates that the circadian clock modulates renal function and identifies the 20-HETE synthesis pathway as one of its principal renal targets. It also suggests that the circadian clock affects BP, at least in part, by exerting dynamic control over renal sodium handling. Recent evidence indicates that the circadian clock is involved in BP control. In mice, suppression or decrease of the circadian clock activity via deletion of the circadian transcriptional activators Bmal1, Clock, or Npas2 leads to low BP, whereas its constitutive activation via deletion of the circadian repressors Cry1 and Cry2 results in salt-sensitive hypertension. 1-4 Wang et al. have recently shown that mice simultaneously devoid of three prolineand acidic amino acid-rich basic leucine zipper circadian transcriptional factors Dbp, Hlf, and Tef exhibit a significant reduction in BP. 5 Maintaining BP within the normal range strongly depends on the capacity of the kidney to precisely regulate sodium content in the extracellular space. Thus, dysregulation of molecular mechanisms involved in renal sodium handling could be partially responsible for the elevated or decreased BP observed in mice with genetically altered clocks. This hypothesis is supported by evidence in humans suggesting that alteration of circadian rhythms of urinary sodium excretion is the primary cause of disease in several forms of hyper-or hypotension. For instance, a decreased renal capacity to excrete sodium during the daytime correlates with nocturnal hypertension, whereas increased sodium excretion during the nighttime contributes to the maintenance of orthostatic hypotension. 6,7 Of note, important changes in the amplitude or the circadian phase of urinary excretion of sodium can be provoked not only by a pathologic process but also by a misalignment between the endogenous circadian clock and the imposed rest-activity or feeding cycles, or by sleep disturbance. For instance, Kamperis et al. have shown that acute sleep deprivation in humans leads to excessive natriuresis and kaliuresis during the subjective night and attenuation of the

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

The Circadian Clock Modulates Renal Sodium Handling

Nikolaeva

Pradervand

Centeno³

et al. 2012

Journal of the American Society of Nephrology

124

122

View full text Add to dashboard Cite

show abstract

“…It is likely that closure of BK Ca accounts for the remaining BP effects of 20-HETE in the male TRPV1 KO and female WT mice, rather than to its documented effects on renal sodium transport. 22 Importantly, differences in BK Ca expression and activity have been previously excluded as underlying sex differences in vascular reactivity. 25 The activity of 20-HETE at TRPV1 is likely to be a phenomenon common to several vascular beds innervated by sensory C-fibers, including the coronary 26 and splanchnic 27 circulations.…”

Section: Discussionmentioning

confidence: 99%

“…2,3,22 The exact molecular pathways mediating the vasoactive effects of 20-HETE are uncertain: a fact particularly compounded by the lack of identification, to date, of a credible receptor for this ligand. 20-HETE-induced phosphorylation of smooth muscle BK Ca , resulting in channel closure, is thought to mediate, in part, 20-HETE-induced constriction, although direct binding of 20-HETE to BK Ca has not been proposed.…”

Section: Discussionmentioning

confidence: 99%

Activation of Neuronal Transient Receptor Potential Vanilloid 1 Channel Underlies 20-Hydroxyeicosatetraenoic Acid–Induced Vasoactivity

et al. 2013

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Abstract-A rise in intraluminal pressure triggers vasoconstriction in resistance arteries, which is associated with local generation of the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE). Importantly, dysregulation of 20-HETE synthesis and activity has been implicated in several cardiovascular disease states, including ischemic disease, hypertension, and stroke; however, the exact molecular pathways involved in mediating 20-HETE bioactivity are uncertain. We investigated whether 20-HETE activates the transient receptor potential vanilloid 1 (TRPV1) and thereby regulates vascular function and blood pressure. We demonstrate that 20-HETE causes dose-dependent increases in blood pressure, coronary perfusion pressure (isolated Langendorff), and pressure-induced constriction of resistance arteries (perfusion myography) that is substantially attenuated in TRPV1 knockout mice and by treatment with the neurokinin 1 receptor antagonist RP67580. Furthermore, we show that both channel activation (via patch-clamping of dorsal root ganglion neurons) and vessel constriction are enhanced under inflammatory conditions, and our findings indicate a predominant role for protein kinase A-mediated sensitization of TRPV1 in these phenomena. Finally, we identify a prominence of these pathway in males compared with females, an effect we relate to reduced protein kinase A-induced phosphorylation of TRPV1. 20-HETE-induced activation of TRPV1, in part, mediates pressure-induced myogenic constriction and underlies 20-HETE-induced elevations in blood pressure and coronary resistance.

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“…604426) encodes an ω-hydroxylase that catalyzes the metabolism of arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE) (1). 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).…”

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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20-Hydroxyeicosatetraeonic Acid: A New Target for the Treatment of Hypertension

Cited by 157 publications

References 169 publications

The Circadian Clock Modulates Renal Sodium Handling

The Circadian Clock Modulates Renal Sodium Handling

Activation of Neuronal Transient Receptor Potential Vanilloid 1 Channel Underlies 20-Hydroxyeicosatetraenoic Acid–Induced Vasoactivity

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

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