Effect of Cytochrome P450 Metabolites of Arachidonic Acid in

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Effect of Cytochrome P450 Metabolites of Arachidonic Acid in Nephrology Fan Fan and Richard J. Roman Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi

ABSTRACT Thirty-five years ago, a third pathway for the metabolism of arachidonic acid by cytochrome P450 enzymes emerged. Subsequent work revealed that 20-hydroxyeicosatetraenoic and epoxyeicosatrienoic acids formed by these pathways have essential roles in the regulation of renal tubular and vascular function. Sequence variants in the genes that produce 20-hydroxyeicosatetraenoic acid are associated with hypertension in humans, whereas the evidence supporting a role for variants in the genes that alter levels of epoxyeicosatrienoic acids is less convincing. Studies in animal models suggest that changes in the production of cytochrome P450 eicosanoids alter BP. However, the mechanisms involved remain controversial, especially for 20-hydroxyeicosatetraenoic acid, which has both vasoconstrictive and natriuretic actions. Epoxyeicosatrienoic acids are vasodilators with anti-inflammatory properties that oppose the development of hypertension and CKD; 20-hydroxyeicosatetraenoic acid levels are elevated after renal ischemia and may protect against injury. Levels of this eicosanoid are also elevated in polycystic kidney disease and may contribute to cyst formation. Our review summarizes the emerging evidence that cytochrome P450 eicosanoids have a role in the pathogenesis of hypertension, polycystic kidney disease, AKI, and CKD. J Am Soc Nephrol 28: 2845–2855, 2017. doi: https://doi.org/10.1681/ASN.2017030252

At the time that the Nobel Prize was awarded for the discovery of PGs, other investigators reported that arachidonic acid (AA) is also metabolized by cytochrome P450 (CYP450) enzymes to 20-hydroxyeicosatetraeonoic acid (20HETE) and epoxyeicosatrienoic acid (EETs). Subsequent studies revealed that they represent the constitutive pathways for the renal metabolism of AA and that 20-HETE and EETs influence both renal tubular and vascular function and arterial pressure. The formation of 20-HETE is catalyzed by enzymes of the CYP4A and CYP4F families (Figure 1).1–4 CYP4A11, CYP4F2, and CYP4F3 are the isoforms that produce 20-HETE in humans. 5–8 CYP4A1, CYP4A2, CYP4A3, CYP4A8, CYP4F1, J Am Soc Nephrol 28: 2845–2855, 2017

and CYP4F4 are the corresponding isoforms in rats.1,3,9–13 CYP4A10, CYP4A12a, CYP4A12b, and CYP4A14 are expressed in mice, but only CYP4A12a metabolizes AA to 20-HETE.14–17 20-HETE is metabolized by alcohol dehydrogenase to the carboxylic acid, which undergoes further metabolism by b-oxidation.18,19 20-HETE is also a substrate for epoxygenases, lipoxygenases, and cyclooxygenases (COXs).20,21 It is conjugated by UDP-glucuronosyltransferases22 and excreted as a glucuronide in humans. Enzymes of the CYP2C8, CYP2C9, and CYP2J2 families catalyze the formation of EETs in humans (Figure 1). CYP2C23 and CYP2C44 are the corresponding homologs in rats and mice, respectively.23 EETs have short half-lives and are converted to less active dihydroxyeicosatrienoic acids

by soluble epoxide hydrolase (sEH).2,24,25 Some are metabolized by COX to a vasoconstrictor and by b-oxidation to shorterchain inactive products.24,26,27 EETs also undergo v-hydroxylation by CYP4A and CYP4F enzymes. The epoxy alcohols formed activate the peroxisome proliferator–activated a-receptor that may contribute to some of the anti-inflammatory and angiogenic properties of EETs.23 A summary of the effects of 20-HETE and EETs is presented in Figure 2. 20HETE is a potent vasoconstrictor that recently has been shown to increase vascular tone and promote endothelial dysfunction by activating a chemokine, RANTES/CCL5, and G-protein receptor 75 (GPR75) that signals through the Gaq/11/PLC/PKC and c-Src/EGF receptor (EGFR) pathways.28,29 The vasoconstrictor response to 20-HETE is associated with activation of mitogen-activated protein kinases,30 protein kinase C,31 and Rho and tyrosine kinases31,32 to promote calcium entry by inhibiting the large conductance calcium-sensitive potassium channel and activating the transient receptor potential canonical 6 (TRPC6) and L-type calcium channels.3,33–35 Elevations in transmural pressure increase

Published online ahead of print. Publication date available at www.jasn.org. Correspondence: Dr. Richard J. Roman, Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216. Email: rroman@ umc.edu Copyright © 2017 by the American Society of Nephrology

ISSN : 1046-6673/2810-2845

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Figure 1. CYP450 pathways for the formation of 20-HETE and EETs. AA esterified into membrane phospholipids is released via cytoplasmic phospholipase A2 (cPLA2) after membrane stretch or through the action of hormones and autacoids. Free AA is metabolized via CYP450 enzymes of the CYP2C and CYP2J families to EETs and by CYP4A or CYP4F enzymes to 20-HETE. EETs are hydrolyzed to dihydroxyeicosatrienoic acids (DHETs) by sEH. 20-HETE is metabolized to shorter-chain carboxylic acids by alcohol dehydrogenase (ADH) and b-oxidation, by COX2 to 20-hydroxy-PG, and by 12-lipoxygenase (12-LOX) to 12,20-hydroxy-eicosatrienoic acid. It also can be conjugated by uridine glucuronosyltransferase (UGT), filtered, and excreted in the urine.

opening of large conductance calciumsensitive potassium channels in vascular smooth muscle24,64,65 and TRPC3/6 and intermediate calcium-activated potassium channels in the endothelium. 62 They mediate the NO- and COX-independent vasodilator responses of the Af-art to acetylcholine, bradykinin, and adenosine. 24 EETs promote sodium excretion by inhibiting the Na + /H + exchanger in the PT and the epithelial sodium channel (ENaC) in the cortical collecting duct (CCD).4,66,67 They contribute to the natriuretic actions of ANG II and dopamine in the PT. 3,67 The expression of CYP2C23 and CYP2C44 in the CCD increases in rodents fed high-sodium or -potassium diets,67–69 which suppresses ENaC activity to maintain sodium balance.70 Administration of epoxygenase inhibitors67 or knockout of CYP2C44 increases ENaC activity and causes salt-sensitive hypertension.68–70

CYP450 METABOLITES AND HYPERTENSION Human Genetic Studies

20-HETE production,36 and blockade of 20-HETE synthesis diminishes myogenic tone in renal and cerebral arteries.2,3,37 20-HETE inhibitors block the myogenic and tubuloglomerular feedback responses of the afferent arteriole (Af-art)38,39 and impair autoregulation of renal blood flow.40 20-HETE formation is stimulated by angiotensin II (ANG II),33,41,42 endothelin,41,43–45 and serotonin.46,47 20-HETE inhibitors attenuate the subsequent vasoconstrictor responses by 50%.33,46,48 Increases in vascular 20-HETE activate the renin-angiotensin system by increasing expression of angiotensin-converting enzyme.49,50 It also promotes endothelial dysfunction by uncoupling eNOS and increasing oxidative stress.50–52 Upregulation of vascular 20-HETE production with a CYP4A2 lentivirus increased endothelial expression of angiotensin-converting enzyme and produced ANG II–dependent hypertension.53 20-HETE formation is inhibited by nitric oxide (NO), carbon monoxide, and superoxide. 54,55 The cGMP-independent effects of NO on 2846

potassium channels and vascular tone are mediated by a fall in 20-HETE levels.56 20-HETE is a natriuretic agent that inhibits Na+/K+-ATPase activity and sodium transport in the proximal tubule (PT)1–3,57,58 and thick ascending loop of Henle (TALH).59 It promotes internalization of the sodium-hydrogen exchanger 3 in the PT after elevations in renal perfusion pressure60 and blocks apical K + channels in the TALH that limit Na+ and K+ uptake via the Na-KCl cotransporter. 1–3,59 Elevations in renal perfusion pressure increase 20-HETE formation, which partially mediate the pressure natriuretic response.60,61 20-HETE also contributes to the natriuretic effects of parathyroid hormone, dopamine, endothelin, and ANG II in the PT.3,35 EETs (Figure 2) act as endotheliumderived relaxing factors with natriuretic, antihypertensive, antiapoptotic, and anti-inflammatory properties.62,63 They are potent vasodilators that activate a Gs protein–linked receptor to facilitate the

Journal of the American Society of Nephrology

Functional variants in CYP4F2 and CYP4A11 have been linked to hypertension in black Americans, white Americans, Chinese, German, Swedish, and Australian cohorts.8,71–80 The V433M variant75 in CYP4F2 and the T8590C variant8 in CYP4A11 decrease enzyme activities. The T8590C variant in CYP4A11 is associated with reduced urinary 20-HETE excretion and salt-sensitive hypertension.72,81 Paradoxically, the urinary excretion of 20-HETE glucuronide is increased in patients who are hypertensive carrying the mutant CYP4F2 allele.76,77 It was suggested that elevated renal 20-HETE production increases BP secondary to renal vasoconstriction. However, this hypothesis no longer seems tenable, because recent data indicate that urinary 20HETE is filtered and excreted rather than the view that urinary 20-HETE reflects intrarenal production.82 CYP2C8, CYP2C9, and CYP2J2 are the primary epoxygenases that produce EETs. Inactivating variants in CYP2C8*3, CYP2C9*2, CYP2C9*3, and CYP2J2*7 are J Am Soc Nephrol 28: 2845–2855, 2017

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Figure 2. Renal and vascular actions of 20-HETE and EETs. 20-HETE and EETs are formed in the kidney and renal and peripheral arterioles. The positive and negative modulatory effects of EETs and 20-HETE on various aspects of vascular and renal function are indicated by up and down arrows. IR, ischemia-reperfusion; RBF, renal blood flow; TGF, tubuloglomerular feedback.

not linked to hypertension in black83 and Swedish populations.84,85 A CYP2J2*7 variant that reduces EETs has been associated with hypertension in a Russian population,86 white men but not white women, and women in a Han population.85,87,88 It is more strongly associated with coronary artery disease and myocardial infarctions. 89–91 Other studies indicate that variants in sEH are associated with endothelial dysfunction, myocardial infarction, and stroke62,63 but not hypertension.24,67,84,87,92,93 These studies indicate that inactivating mutations in CYP4A11 or CYP4F2 are linked to hypertension, whereas the evidence supporting a role for genetic variants that reduce EETs is less consistent. However, the mechanisms involved remain unsettled, because both increases and decreases in 20-HETE are associated with hypertension. 20-HETE and Hypertension

Sacerdoti et al.94 first reported that the 20-HETE production is elevated in the spontaneously hypertensive rat (SHR). Subsequent studies revealed that CYP4A2 mRNA is overexpressed95 and that renal and vascular 20-HETE production is elevated in SHR.96–100 20-HETE inhibitors attenuate hypertension in male98–103 and postmenopausal female SHRs.104 Similar results have been described in rats treated with dihydrotestosterone, which increases J Am Soc Nephrol 28: 2845–2855, 2017

20-HETE production via the androgen receptor.105–107 Inhibition of 20-HETE production also lowers BP in ANG II and endothelin-induced hypertensive models.2,108 The strongest evidence supporting the hypertensive actions of 20-HETE is derived from studies using genetically manipulated mouse models. Transgenic expression of CYP4A11 and CYP4F2 enhances renal 20-HETE production and increases BP. 109–112 Knockout of CYP4A1414,16,113,114 induces male-specific hypertension associated with an off-target increase in plasma testosterone that increases 20-HETE formation, similar to what is seen in animals treated with dihydrotestosterone.14–17 These effects were blocked by castration14 or 20HETE inhibitors. More recently, Wu et al.16 reported that CYP4A12 transgenic mice develops salt-resistant hypertension associated with increases in renal and vascular 20-HETE production, oxidative stress, endothelial dysfunction, and enhanced vascular reactivity, which were reversed by 20-HETE blockade. However, transgenic mice expressing human CYP4A11 develop salt-sensitive hypertension associated with an increase in renal angiotensinogen and Na+-Cl2 cotransporter expression, which is reversed by administration of an AT1 receptor blocker, a 20-HETE antagonist, or a thiazide diuretic.112 This suggests that the

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effect of 20-HETE on Na+-Cl2 cotransporter might be secondary to activation of the intrarenal renin-angiotensin system. In contrast, Dahl salt-sensitive (Dahl S) rats, which have reduced 20-HETE levels in the kidney and vasculature, also develop salt-sensitive hypertension. 11,115–11 8 Unlike normotensive strains, they do not increase epoxygenase activity when fed a high-salt diet.63,119 They exhibited an impaired pressure natriuresis response120 and elevated Na-KCl cotransporter and ENaC activity in the TALH and CCD,62,63 respectively. Induction of renal 20-HETE and EETs production with fibrates23,63 or transfer of wild-type CYP4A alleles improves pressure natriuresis and opposes the development of hypertension.11,117 Fenofibrate also enhances renal 20-HETE levels and attenuates hypertension in ANG II–infused mice, Ren-2 hypertensive rats, and stroke-prone SHR or SHR.121–124 A summary of the roles of 20-HETE and EETs in hypertension is presented in Figure 3. We hypothesize that decreases in the renal formation of 20-HETE in Dahl S rats and patients with inactivating mutations in CYP4A11 and CYP4F2 promote the development of salt-sensitive hypertension. This is associated with impaired myogenic and tubuloglomerular feedback responses in the Af-art in Dahl S rats, 1 2 5 , 1 2 6 which increase glomerular pressure and trigger renal injury that sustains the hypertension. Autoregulation of cerebral blood flow is also impaired, which may contribute to loss of cognitive function. 37 However, renal and vascular 20-HETE production is elevated in SHRs, ANG II– and androgeninduced hypertensive rodents, and CYP4A14 knockout and CYP4A12 transgenic mice. 16,53,105–107,124 These models develop hypertension that is not salt sensitive but is with associated endothelial dysfunction and elevated vascular reactivity in the renal and peripheral vasculature. The increase in renal vascular resistance shifts the pressurenatriuretic relationship to higher pressures and opposes the development of renal injury. CYP Eicosanoids and Kidney Disease

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Figure 3. Role of 20-HETE and EETs in hypertension. The renal and vascular production of 20-HETE is altered in various genetic and experimental rodent models of hypertension and CYP4A, CYP4F, and CYP2C transgenic and knockout (KO) mouse models. Models associated with decreases in the formation of EETs and 20-HETE are indicated in blue and green, respectively, and those associated with increases are indicated in black. Elevations in the vascular formation of 20-HETE increase renal and peripheral vascular resistance and produce salt-insensitive forms of hypertension, whereas decreases in the formation of 20-HETE and EETs increase sodium transport and promote salt-sensitive hypertension. DHT, dihydrotestosterone; ET1, endothelin 1; L-NAME, N(v)-nitro-L-arginine methyl ester.

EETs and Hypertension

Studies using transgenic and knockout mouse models, sEH inhibitors, and EETs analogs have provided unequivocal evidence of the antihypertensive effects of EETs (Figure 3).2,23,62,63 ANG II– or L-NAME–induced hypertension is attenuated in transgenic mice expressing human endothelial CYP2J2 or CYP2C8. This was associated with increased EETs levels that enhanced the Af-art response to acetylcholine and impaired the vasoconstrictor response to endothelin.127 Similarly, inhibition or knockout of sEH enhances EETs production and opposes the development of ANG II, L-NAME, and DOCA salt models of hypertension.64,128–131 Administration of epoxygenase inhibitors or knockout of CYP2C44 is associated with decreased renal EETs, elevated ENaC activity in the CCD, and salt-sensitive hypertension that is reversed by amiloride.67–69 Knockout of CYP4A10 also produces salt-sensitive hypertension due to suppression of 2848

CYP2C44 and renal EETs rather than inhibition of 20-HETE.132

CYP450 METABOLITES OF AA AND CKD 20-HETE

Decreased levels of renal 20-HETE and EETs in Dahl S rats promote sodium retention and the development of saltsensitive hypertension. The decrease in 20-HETE also impairs the myogenic and tubuloglomerular feedback responses of the Af-art, elevates glomerular capillary pressure, increases the permeability of the glomerulus to albumin (Palb), and upregulates the expression of TGF-b leading to the development of proteinuria and CKD.11,117,133 Normalization of the 20-HETE levels with fibrates or transfer of wild-type CYP4A genes in congenic Dahl S strains11,115–117,134 prevented the development of proteinuria and renal injury. We hypothesize that


the deficiency in renal 20-HETE may play a similar role in the development of hypertension and kidney injury in patients with inactivating mutations in CYP4A11 and CYP4F2. 20-HETE is also produced by the glomerulus and podocytes.135,136 TGF-b inhibits 20-HETE production and increases Palb in isolated glomeruli.133,134 Chronic blockade of 20-HETE increased Palb and proteinuria in normotensive rats. 1 3 4 , 1 3 5 More recently, McCarthy et al.137 reported that increased 20-HETE levels in CYP4A14 knockout mice protected podocytes from the detrimental effects of ethanol by blocking superoxide production. Glomerular 20-HETE production is reduced in diabetic rats, and induction of 20-HETE and EETs formation with fibrates reduced proteinuria and renal injury.138 The finding that 20-HETE excretion was correlated with the decline in eGFR82 in black patients who were diabetic is also consistent with a glomerular protective action. Hyperglycemia increases 20-HETE production in mouse podocytes136 and rat epithelial cells 139 and enhances 20-HETE–dependent reactive oxygen species (ROS) formation and apoptosis. CYP4A and NADPH oxidase expression is upregulated in glomeruli of diabetic OVE26 mice. Blockade of 20-HETE decreased ROS and ameliorated apoptosis and albuminuria.136 Thus, 20-HETE has been suggested to contribute to diabetic nephropathy. 138,140–142 Roshanravan et al.143 recently reported that 20-HETE increases TRPC6 activity in podocytes secondary to activation of ROS production. Activation of TRPC6 causes foot process effacement,144–147 but paradoxically, effacement prevents podocyte detachment.148 Thus, the net effects of 20-HETE activation of the TRPC6 channels in podocytes on the glomerular filtration barrier remains to be determined. EETs

EETs have antihypertensive properties and protect against renal and vascular injury by reducing inflammation, oxidative stress, and endothelial dysfunction.1–3,62,63 Exogenous 8, 9 EET has a J Am Soc Nephrol 28: 2845–2855, 2017

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direct protective effect on the glomerulus.149 Inhibition or knockout of sEH increases the production of EETs and reduces proteinuria, glomerular injury, and renal inflammation in animals with unilateral urinary obstruction, diabetic- and obesity-induced nephropathy, reduced renal mass ANG II, and DOCA-salt hypertension.24,62,63,140,150 Administration of EET agonists or upregulation of EETs formation in CYP2J2 transgenic mice or after administration of a CYP2J2 viral vector reduced proteinuria, renal inflammation, and glomerular injury in STZ diabetic or ANG II hypertensive mice141,151 and reduced renal mass rats.152 An orally active analog prevented the development of glomerular injury and proteinuria in Dahl S rats without altering BP.153 The common protective effects of EETs in all of these models of CKD are reduced oxidative stress and inflammation. Thus, sEH inhibitors and EETs agonists have emerged as promising therapeutic targets for the treatment of CKD.

CYP450 METABOLITES, AKI, AND RENAL TRANSPLANTATION

HETE levels by transfer of wild-type CYP4A genes on chromosome 5 in SS.5BN consomic or SS.5Lew 4A+ congenic rats also protected against renal IRI.158 However, another study indicated that inhibition of 20-HETE protects against IRI in acutely uninephrectomized rats.159 The reason for the contradictory results is uncertain, but it is likely related to the different experimental models, because a subsequent study157 reported that 20-HETE inhibition reduced IRI in uninephrectomized rats but had the opposite effect using the bilateral ischemic model. Given the renoprotective and antiinflammatory effects of EETs, it is surprising that there have not been more studies to examine their effects in models of AKI. Cisplatin-induced nephrotoxicity was attenuated in sEH knockout mice,161 whereas an EET agonist ameliorated cyclosporin- and radiation-induced nephropathy in rats.162,163 More recently, the effects of EETs on the renal IRI were examined. The renal EET-to-DiHETE ratio was elevated in sEH knockout mice, but unexpectedly, plasma creatinine concentration and the degree of IRI were greater than in controls.164 Transplant

AKI

Ischemia-reperfusion injury (IRI) is the most common cause of AKI.1,154,155 Renal 20-HETE production is elevated after renal ischemia.156–159 20-HETE has numerous effects on renal tubular and vascular function that can alter IRI. It could prolong vasoconstriction after reperfusion and augment IRI. It increases oxidative stress and the release of inflammatory cytokines and potentiates IRI in renal epithelial cells.160 However, 20HETE could attenuate IRI by increasing medullary oxygenation, because it increases medullary blood flow and inhibits tubular sodium transport.156,157 Administration of a 20-HETE agonist was found to prevent the secondary fall in medullary blood flow and medullary hypoxia and reduce IRI after bilateral renal ischemia. 156–159 Similarly, Dahl S rats that have a deficiency in renal 20HETE are more susceptible to renal IRI than other strains. Increasing renal 20J Am Soc Nephrol 28: 2845–2855, 2017

Plasma 20-HETE levels increased shortly after renal transplantation, and it was a positive predictor of graft function.165,166 It was suggested to serve as an early biomarker of allograft function. More recently, inactivating variants in CYP4F2 and CYP4A11 were associated with delayed graft function and post-transplant diabetes mellitus.167,168 Similarly, variants in CYP2C8, CYP2J2, and sEH that reduce levels of EETs are associated with allograft dysfunction.168–170 These results suggest that both 20-HETE and EETs may have a protective role in renal transplant.

CYP450 METABOLITES OF AA AND POLYCYSTIC KIDNEY DISEASE

20-HETE promotes ang iogenesis and proliferation of a variety of cell types.171–174 Its effects on renal epithelial cells are associated with activation of the

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RAF/MEK/extracellular signal–regulated kinase and PI3K-AKT pathways secondary to activation of c-Src and the EGFR.171 It stimulates the production of ROS and inflammatory cytokines.3,28,175,176 Polycystic kidney disease (PKD) is associated with activation of the same pathways. The production of 20-HETE is increased in the kidneys of rodents in PKD models and the sera of patients with PKD.171,177,178 Inhibition of 20-HETE production reduced cyst formation in rodent models, and this was associated with diminished activation of the EGFR and p44/42 mitogen-activated protein kinase and cAMP levels.171,177–179 These studies suggest that 20-HETE may be a potential biomarker and therapeutic target for the treatment of PKD. SUMMARY

Sequence variants in the genes that reduce the production of 20-HETE generally are associated with the development of hypertension, whereas the results for those that alter the production of EETs are inconsistent. Elevations in the formation of 20-HETE increase renal and peripheral vascular resistance and produce salt-insensitive forms of hypertension resistant to renal injury, whereas decreases in the formation of 20-HETE increase and promote saltsensitive hypertension and renal injury. 20-HETE levels are elevated after renal ischemia and may protect against injury. They are also elevated in PKD. Thus, 20HETE agonists or antagonists may be useful for these conditions. EETs have antihypertensive and anti-inflammatory properties. Decreases in the formation of EETs promote salt-sensitive hypertension. They are renoprotective in models of CKD by reducing oxidative stress and inflammation. Thus, inhibitors of sEH and orally active EETs agonists are considered promising therapies for hypertension and diabetic nephropathy.

ACKNOWLEDGMENTS This study was supported by grants AG050049 (to F.F.), P20GM104357 (pilot: to F.F.; cores B CYP Eicosanoids and Kidney Disease

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and C: to R.J.R.), HL36279 (to R.J.R.), and DK104184 (to R.J.R.) from the National Institutes of Health and grant 16GRNT31200036 (to F.F.) from the American Heart Association.

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