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20-Hydroxyeicosatetraenoic acid, a far-reaching autacoid in chronic kidney disease

hypertension and beyond

Zoccali, Carminea; Mallamaci, Francescaa; Grassi, Guidob , c

doi: 10.1097/HJH.0000000000000678
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aCNR-IFC, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, Reggio Calabria

bClinica Medica, Dipartimento di Scienze della Salute, Università Milano-Bicocca

cIRCCS Multimedica, Sesto San Giovanni, Milano, Italy

Correspondence to Carmine Zoccali, CNR-IBIM Research Unit and Nephrology, Dialysis and Renal Transplantation Unit, Ospedali Riuniti, Reggio Calabria, Italy. E-mail: carmine.zoccali@tin.it

A PubMed search with the term 20-hydroxyeicosatetraenoic acid (20-HETE) made on 26 April 2015 produced 569 original articles, that is, just a tiny fraction of the number of hits of the whole class of signaling molecules made by oxidation of 20-carbon fatty acids, the term ‘eicosanoid(s)’ (122 049 hits). Even though it rarely makes headlines, 20-HETE is an unquestionably relevant factor in the control of the cardiovascular system and the kidney [1]. Mutations in CYP4A11, a key enzyme for 20-HETE synthesis, have been linked to elevated blood pressure (BP) in salt-sensitive hypertensive humans [2]. As the risk allele for high BP by this gene is transmitted randomly at gamete formation, this observation based on ‘Mendelian randomization’ most likely underlies a true causal link between this enzyme that regulates 20-HETE and human hypertension. 20-HETE has wide ranging biologic actions, including cell proliferation and angiogenesis (Fig. 1). Inhibitors of the synthesis of 20-HETE block various growth factors and reduce tumors’ progression [3] and recent studies show that these compounds may mitigate cysts enlargement in polycystic kidney disease [4]. 20-HETE, is an ω-hydroxylated eicosanoid that derives from arachidonic acid. The biochemical pathways parented by arachidonic acid are sketched in Fig. 1. Enzymes belonging to the CYP4A gene family are highly expressed in the liver and the kidney has significant levels of CYP4A, particularly in the cortex.

FIGURE 1

FIGURE 1

Coherent experimental evidence exists that 20-HETE is an important factor in the renal regulation of sodium excretion and in the long-term control of arterial pressure in various experimental models [1]. 20-HETE is a powerful inhibitor of tubular Na+/K+-ATPase activity and a strong vasoconstrictor in kidney microvessels [5]. It is synthesized at various sites along the nephron including the proximal tubule, the thick ascending loop and renal arterioles both in the cortex and outer medulla. This eicosanoid is fully integrated with major factors regulating vascular tone, including angiotensin II [6], the sympathetic neurotransmitter nor epinephrine [7], and a major vasoconstrictor autacoid such as endothelin [7]. Interference with the renal synthesis of 20-HETE in the rat in vivo disturbs blood flow autoregulation and tubuloglomerular feedback, reduces chloride transport and affects long-term BP control [1]. The effect of 20-HETE on BP in the rat is strain specific. Indeed, high 20-HETE is an active player in hypertension in the spontaneously hypertensive rat [8], whereas in a quintessential model of salt-sensitive hypertension such as in the Dahl rat, lower – rather than higher – renal synthesis of this eicosanoid goes along with hypertension [9]. Such an apparent discrepancy may depend on the fact that in the first model 20-HETE synthesized in excessive amounts in arterioles may trigger hypertension by a direct vasoconstrictor mechanism and/or by potentiating the effect of other vasoconstrictors, whereas in the Dahl rat deficient 20-HETE synthesis at critical tubular sites impairs sodium excretion thereby generating sodium-dependent hypertension.

N-3 fatty acids (n-3FA, also called ω-3 fatty acids) are a key intervention to modify arachidonic acid derived compounds that may have a negative impact on human health. n-3FA reduce the synthesis of vasoconstrictive and platelet proaggregant compounds such as thromboxane and of prostaglandin-like compounds formed in vivo via free radical-initiated peroxidation of arachidonic acid (F2-isoprostanes). Randomized clinical trials consistently show that n-3FA lower BP in hypertensive patients. A meta-analysis published in 2014 including 70 trials documented significant but small effects of n-3FA on BP (−1.52/-2.25 mm Hg) [10]. However, analyses focusing in untreated hypertensive individuals revealed a much more pronounced effect (4.5/3.0 mmHg) providing strong support to the contention that interference with the arachidonic acid pathway has meaningful therapeutic potential. This pathway is indeed a possible route whereby n-3FA may reduce arterial pressure [11]. To date, there is no information on this potentially important mechanism in human hypertension. Investigators at the University of Western Australia in Perth (Trevor A Mori group) in 2009 published in the Journal a randomized trial testing the effect n-3FA on BP in chronic kidney disease (CKD) [12], a population with a high prevalence of salt-sensitive hypertension [13]. In this double-blind, placebo-controlled trial, 85 patients with an average glomerular filtration rate of 36 ml/min (i.e. patients with moderate to severe CKD) were randomized to receive n-3FA (4 g) or coenzyme Q (CoQ, a factor with purported antihypertensive and endothelium-protective effects), n-3FA and CoQ combined, or a placebo (4 g olive oil) for 8 weeks. In this trial, n-3FA, but not CoQ, reduced BP by −3.3/−2.9 mmHg, which is a not trivial reduction. Importantly, such an effect was additive to that of antihypertensive agents (mainly angiotensin-converting enzyme inhibitors) because these drugs were maintained during the trial. The lack of effect of CoQ came as no surprise because a meta-analysis by the Cochrane collaboration largely failed to confirm the hypothesis that CoQ has a significant antihypertensive effect in human hypertension [14]. Dr Ann Barden and the authors of this trial [12] make treasure of the biological bank of the same trial by performing a new analysis, whose results are published in the present issue of the Journal[15], aimed at investigating the effect of n-3FA on plasma 20-HETE and at testing the hypothesis that changes in this parameter are key to explain the BP-lowering effect of n-3FA. In line with this hypothesis, 20-HETE plasma levels were by about the 29% lower in patients randomized to n-3FA supplementation than in those who did not receive n-3FA. Furthermore, a similar difference between the active and the control arm (−22% in n-3FA-treated patients) emerged for plasma F2-isoprostanes levels, a reliable metric of oxidative stress [15]. No effect of n-3FA supplementation was apparent on the renal excretion of 20-HETE. The fractional renal excretion of 20-HETE was very modest indeed (<1%) in another recent study but much higher in African–American patients with CKD than in healthy controls of the same race [16]. Overall, results of this randomized trial are compatible with the interpretation that the favorable effect of n-3FA on BP depends on the vascular (direct) effect of this eicosanoid rather than on its renal effects. Importantly, the size effect of n-3FA on plasma 20-HETE and F2-isoprostanes was large that makes these secondary analyses of particular interest because high 20-HETE and oxidative stress are suspected to play a role in hypertension in CKD patients [1]. In addition to face-to-face comparison of 20-HETE levels in n-3FA-treated and n-3FA-untreated patients, the authors performed various exploratory analyses in well conceived regression models. The most relevant finding in these hypothesis-generating secondary analyses was that 20-HETE levels after 8 weeks of n-3FA supplementation associated directly with 24-h ambulatory blood pressure measurement (ABPM) and, even more strongly, with daytime ABPM [15]. Thus, n-3FA treatment may expose a 20-HETE-dependancy of arterial pressure control in hypertensive patients. Although of heuristic relevance, this observation falls short of proving causality. Other analyses in the same study showed no association between 20-HETE changes and BP changes across the trial, whereas at baseline 20-HETE was inversely – rather than directly – associated with daytime SBP. Novel analyses by Barden et al.[15], demand further experimental studies. To test whether the reduction in plasma 20-HETE levels is causally involved in the BP-lowering effect of n-3FA, a specific intervention on this eicosanoid during n-3FA supplementation is needed. In other words, if 20-HETE is a key factor in the hypotensive response to n-3FA, one would expect that such a hypotensive response be prevented by a cointervention (20-HETE infusion) maintaining the plasma 20-HETE concentration at constant levels. Experimental studies of the kind can be envisaged in the remnant kidney model (rats with 4/5 surgical ablation of renal mass), which is considered a reliable animal model of CKD.

In conclusion, secondary analyses in a trial testing the effect of n-3FA supplementation on BP control in CKD patients with moderate-to-severe CKD [15] suggest that reduction in 20-HETE levels may be a fundamental metabolic step mediating the hypotensive effect of n-3FA in these patients. 20-HETE is an inherently pleiotropic compound that impinges also on cell proliferation and on renal fibrosis [1]. Well beyond hypertension, focusing attention on this eicosanoid may have far-reaching implications in hypertension and CKD research.

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ACKNOWLEDGEMENTS

Conflicts of interest

There are no conflicts of interest.

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