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Effect of Metabolites of 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 soluble hydrolase (sEH).2,24,25 by cytochrome P450 emerged. Subsequent work revealed that 20-hydrox- Some are metabolized by COX to a vaso- yeicosatetraenoic and epoxyeicosatrienoic acids formed by these pathways have constrictor and by b-oxidation to shorter- essential roles in the regulation of renal tubular and vascular function. Sequence chain inactive products.24,26,27 EETs also variants in the that produce 20-hydroxyeicosatetraenoic acid are associated undergo v-hydroxylation by CYP4A and with in humans, whereas the evidence supporting a role for variants in CYP4F enzymes. The epoxy alcohols the genes that alter levels of epoxyeicosatrienoic acids is less convincing. Studies in formed activate the peroxisome prolifera- animal models suggest that changes in the production of cytochrome P450 eicosa- tor–activated a- that may contrib- noids alter BP. However, the mechanisms involved remain controversial, especially utetosomeoftheanti-inflammatory and for 20-hydroxyeicosatetraenoic acid, which has both vasoconstrictive and natri- angiogenic properties of EETs.23 uretic actions. Epoxyeicosatrienoic acids are vasodilators with anti-inflammatory A summary of the effects of 20-HETE properties that oppose the development of hypertension and CKD; 20-hydroxyei- andEETsispresentedinFigure2.20- cosatetraenoic acid levels are elevated after renal ischemia and may protect against HETE is a potent vasoconstrictor that injury. Levels of this are also elevated in polycystic kidney disease and recently has been shown to increase vas- may contribute to cyst formation. Our review summarizes the emerging evidence cular tone and promote endothelial dys- that cytochrome P450 have a role in the pathogenesis of hypertension, function by activating a chemokine, polycystic kidney disease, AKI, and CKD. RANTES/CCL5, and G-protein receptor 75 (GPR75) that signals through the J Am Soc Nephrol 28: 2845–2855, 2017. doi: https://doi.org/10.1681/ASN.2017030252 Gaq/11/PLC/PKC and c-Src/EGF receptor (EGFR) pathways.28,29 The vasoconstric- tor response to 20-HETE is associated with activation of mitogen-activated pro- AtthetimethattheNobelPrizewas and CYP4F4 are the corresponding iso- tein kinases,30 protein kinase C,31 and awarded for the discovery of PGs, other forms in rats.1,3,9–13 CYP4A10, CYP4A12a, Rho and tyrosine kinases31,32 to promote investigators reported that arachi- CYP4A12b, and CYP4A14 are expressed in calcium entry by inhibiting the large con- donic acid (AA) is also metabolized by mice, but only CYP4A12a metabolizes AA ductance calcium-sensitive potassium cytochromeP450(CYP450)enzymesto to 20-HETE.14–17 20-HETE is metabolized channel and activating the transient re- 20-hydroxyeicosatetraeonoic acid (20- by to the carboxylic ceptor potential canonical 6 (TRPC6) HETE) and acid, which undergoes further metabolism – and L-type calcium channels.3,33 35 Eleva- (EETs). Subsequent studies revealed by b-oxidation.18,19 20-HETE is also a sub- tions in transmural pressure increase that they represent the constitutive strate for , lipoxygenases, and pathways for the renal metabolism of (COXs).20,21 It is conju- AA and that 20-HETE and EETs influ- gated by UDP-glucuronosyltransferases22 ence both renal tubular and vascular andexcretedasaglucuronideinhumans. Published online ahead of print. Publication date function and arterial pressure. Enzymes of the CYP2C8, CYP2C9, available at www.jasn.org. The formation of 20-HETE is catalyzed and CYP2J2 families catalyze the formation Correspondence: Dr. Richard J. Roman, De- by enzymes of the CYP4A and CYP4F of EETs in humans (Figure 1). CYP2C23 partment of Pharmacology and Toxicology, Uni- versity of Mississippi Medical Center, 2500 North 1–4 families (Figure 1). CYP4A11, CYP4F2, and CYP2C44 are the corresponding ho- State Street, Jackson, MS 39216. Email: rroman@ and CYP4F3 are the isoforms that produce mologs in rats and mice, respectively.23 umc.edu 5–8 20-HETE in humans. CYP4A1, EETs have short half-lives and are converted Copyright © 2017 by the American Society of CYP4A2, CYP4A3, CYP4A8, CYP4F1, to less active dihydroxyeicosatrienoic acids Nephrology

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opening of large conductance calcium- sensitive potassium channels in vascular smooth muscle24,64,65 and TRPC3/6 and intermediate calcium-activated potas- sium channels in the .62 They mediate the NO- and COX-inde- pendent vasodilator responses of the Af-art to , , 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 con- tribute 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 Figure 1. CYP450 pathways for the formation of 20-HETE and EETs. AA esterified into which suppresses ENaC activity to main- membrane phospholipids is released via cytoplasmic A2 (cPLA2) after tain sodium balance.70 Administration membrane stretch or through the action of and autacoids. Free AA is metabo- of inhibitors67 or knockout lized via CYP450 enzymes of the CYP2C and CYP2J families to EETs and by CYP4A or of CYP2C44 increases ENaC activity and CYP4F enzymes to 20-HETE. EETs are hydrolyzed to dihydroxyeicosatrienoic acids causes salt-sensitive hypertension.68–70 (DHETs) by sEH. 20-HETE is metabolized to shorter-chain carboxylic acids by alcohol de- hydrogenase (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 glu- CYP450 METABOLITES AND curonosyltransferase (UGT), filtered, and excreted in the urine. HYPERTENSION

Human Genetic Studies 20-HETE production,36 and blockade of potassium channels and vascular tone are Functional variants in CYP4F2 and 20-HETE synthesis diminishes myogenic mediated by a fall in 20-HETE levels.56 CYP4A11 have been linked to hyperten- tone in renal and cerebral arteries.2,3,37 20-HETE is a natriuretic agent that sion in black Americans, white Ameri- 20-HETE inhibitors block the myogenic inhibits Na+/K+-ATPase activity and so- cans, Chinese, German, Swedish, and and tubuloglomerular feedback responses dium transport in the proximal tubule Australian cohorts.8,71–80 The V433M of the afferent arteriole (Af-art)38,39 and (PT)1–3,57,58 and thick ascending loop variant75 in CYP4F2 and the T8590C impair autoregulation of renal blood of Henle (TALH).59 It promotes inter- variant8 in CYP4A11 decrease ac- flow.40 20-HETE formation is stimulated nalization of the sodium-hydrogen ex- tivities. The T8590C variant in CYP4A11 by II (ANG II),33,41,42 endo- changer 3 in the PT after elevations in is associated with reduced urinary thelin,41,43–45 and serotonin.46,47 20-HETE renal perfusion pressure60 and blocks 20-HETE excretion and salt-sensitive hy- inhibitors attenuate the subsequent va- apical K+ channels in the TALH that pertension.72,81 Paradoxically, the urinary soconstrictor responses by 50%.33,46,48 limit Na+ and K+ uptake via the Na-K- excretion of 20-HETE glucuronide is in- Increases in vascular 20-HETE activate Cl cotransporter.1–3,59 Elevations in creased in patients who are hypertensive the renin-angiotensin system by increas- renal perfusion pressure increase carrying the mutant CYP4F2 allele.76,77 ing expression of angiotensin-converting 20-HETE formation, which partially It was suggested that elevated renal enzyme.49,50 It also promotes endothelial mediate the pressure natriuretic re- 20-HETE production increases BP second- dysfunction by uncoupling eNOS and in- sponse.60,61 20-HETE also contributes ary to renal . However, this creasing oxidative stress.50–52 Upregula- to the natriuretic effects of parathyroid hypothesis no longer seems tenable, be- tion of vascular 20-HETE production , dopamine, , and cause recent data indicate that urinary 20- with a CYP4A2 lentivirus increased endo- ANG II in the PT.3,35 HETE is filtered and excreted rather than thelial expression of angiotensin-converting EETs (Figure 2) act as endothelium- the view that urinary 20-HETE reflects in- enzyme and produced ANG II–dependent derived relaxing factors with natriuretic, trarenal production.82 hypertension.53 20-HETE formation is antihypertensive, antiapoptotic, and CYP2C8, CYP2C9, and CYP2J2 are inhibited by (NO), carbon anti-inflammatory properties.62,63 They the primary epoxygenases that produce monoxide, and superoxide.54,55 The are potent vasodilators that activate a Gs EETs. Inactivating variants in CYP2C8*3, cGMP-independent effects of NO on protein–linked receptor to facilitate the CYP2C9*2, CYP2C9*3, and CYP2J2*7 are

2846 Journal of the American Society of Nephrology J Am Soc Nephrol 28: 2845–2855, 2017 www.jasn.org BRIEF REVIEW

2 effect of 20-HETE on Na+-Cl cotrans- porter 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 hyperten- sion.11,115–118 Unlike normotensive strains, they do not increase epoxygenase activity when fed a high-salt diet.63,119 They exhibited an impaired pressure na- triuresis response120 and elevated Na-K- Cl cotransporter and ENaC activity in the TALH and CCD,62,63 respectively. In- duction of renal 20-HETE and EETs Figure 2. Renal and vascular actions of 20-HETE and EETs. 20-HETE and EETs are formed in production with fibrates23,63 or transfer the kidney and renal and peripheral arterioles. The positive and negative modulatory effects of of wild-type CYP4A alleles improves EETsand 20-HETEonvariousaspectsofvascularandrenalfunction areindicatedbyupanddown pressure natriuresis and opposes the arrows. IR, ischemia-reperfusion; RBF, renal blood flow;TGF,tubuloglomerularfeedback. development of hypertension.11,117 Fe- nofibrate also enhances renal 20-HETE notlinkedtohypertensioninblack83 and 20-HETE production via the androgen levels and attenuates hypertension in Swedish populations.84,85 A CYP2J2*7 var- receptor.105–107 Inhibition of 20-HETE ANG II–infused mice, Ren-2 hyperten- iant that reduces EETs has been associated production also lowers BP in ANG II sive rats, and -prone SHR or with hypertension in a Russian popula- and endothelin-induced hypertensive SHR.121–124 tion,86 white men but not white women, models.2,108 A summary of the roles of 20-HETE and women in a Han population.85,87,88 The strongest evidencesupporting the and EETs in hypertension is presented in It is more strongly associated with cor- hypertensive actions of 20-HETE is de- Figure 3. We hypothesize that decreases onary artery disease and myocardial in- rived from studies using genetically in the renal formation of 20-HETE farctions.89–91 Other studies indicate manipulated mouse models. Transgenic in Dahl S rats and patients with inac- that variants in sEH are associated with expression of CYP4A11 and CYP4F2 tivating mutations in CYP4A11 and endothelial dysfunction, myocardial in- enhances renal 20-HETE production CYP4F2 promote the development farction, and stroke62,63 but not hyper- and increases BP.109–112 Knockout of of salt-sensitive hypertension. This is as- tension.24,67,84,87,92,93 CYP4A1414,16,113,114 induces male-spe- sociated with impaired myogenic and These studies indicate that inactivat- cific hypertension associated with an tubuloglomerular feedback responses ing mutations in CYP4A11 or CYP4F2 off-target increase in plasma testosterone in the Af-art in Dahl S rats,125,126 are linked to hypertension, whereas the that increases 20-HETE formation, sim- which increase glomerular pressure evidence supporting a role for genetic ilar to what is seen in animals treated and trigger renal injury that sustains variants that reduce EETs is less consis- with dihydrotestosterone.14–17 These ef- the hypertension. Autoregulation of tent. However, the mechanisms involved fects were blocked by castration14 or 20- cerebral blood flow is also impaired, remain unsettled, because both increases HETE inhibitors. More recently, Wu which may contribute to loss of cogni- and decreases in 20-HETE are associated et al.16 reported that CYP4A12 transgenic tive function.37 However, renal and with hypertension. mice develops salt-resistant hypertension vascular 20-HETE production is ele- associated with increases in renal and vated in SHRs, ANG II– and androgen- 20-HETE and Hypertension vascular 20-HETE production, oxidative induced hypertensive rodents, and Sacerdoti et al.94 first reported that the stress, endothelial dysfunction, and en- CYP4A14 knockout and CYP4A12 20-HETE production is elevated in the hanced vascular reactivity, which were transgenic mice.16,53,105–107,124 These spontaneously hypertensive rat (SHR). reversed by 20-HETE blockade. How- models develop hypertension that is Subsequent studies revealed that CYP4A2 ever, transgenic mice expressing human not salt sensitive but is with associated mRNA is overexpressed95 and that renal CYP4A11 develop salt-sensitive hyper- endothelial dysfunction and elevated vas- and vascular 20-HETE production is ele- tension associated with an increase in cular reactivity in the renal and periph- 2 vated in SHR.96–100 20-HETE inhibitors at- renal angiotensinogen and Na+-Cl co- eral vasculature. The increase in renal tenuate hypertension in male98–103 and transporter expression, which is reversed vascular resistance shifts the pressure- postmenopausal female SHRs.104 Similar by administration of an AT1 receptor natriuretic relationship to higher pres- results have been described in rats treated blocker, a 20-HETE antagonist, or a thi- sures and opposes the development of with dihydrotestosterone, which increases azide diuretic.112 This suggests that the renal injury.

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the deficiency in renal 20-HETE may play a similar role in the development of hypertension and kidney injury in pa- tients with inactivating mutations in CYP4A11 and CYP4F2. 20-HETE is also produced by the glo- merulus and podocytes.135,136 TGF-b inhibits 20-HETE production and in- creases Palb in isolated glomeruli.133,134 Chronicblockadeof20-HETEin- creased Palb and proteinuria in normo- tensive rats.134,135 More recently, McCarthy et al.137 reported that increased 20-HETE levels in CYP4A14 knockout mice protected podocytes from the det- rimental effects of ethanol by blocking superoxide production. Glomerular 20-HETE production is reduced in dia- betic rats, and induction of 20-HETE and EETs formation with fibrates re- Figure 3. Role of 20-HETE and EETs in hypertension. The renal and vascular production of duced proteinuria and renal injury.138 20-HETE is altered in various genetic and experimental rodent models of hypertension and The finding that 20-HETE excretion CYP4A, CYP4F, and CYP2C transgenic and knockout (KO) mouse models. Models asso- was correlated with the decline in ciated with decreases in the formation of EETs and 20-HETE are indicated in blue and green, eGFR82 in black patients who were dia- respectively, and those associated with increases are indicated in black. Elevations in the betic is also consistent with a glomerular vascular formation of 20-HETE increase renal and peripheral vascular resistance and pro- protective action. duce salt-insensitive forms of hypertension, whereas decreases in the formation of 20-HETE Hyperglycemia increases 20-HETE and EETs increase sodium transport and promote salt-sensitive hypertension. DHT, dihy- 136 drotestosterone; ET1, endothelin 1; L-NAME, N(v)-nitro-L-arginine methyl ester. production in mouse podocytes and rat epithelial cells139 and enhances 20-HETE–dependent reactive oxygen EETs and Hypertension CYP2C44 and renal EETs rather than in- species (ROS) formation and . Studies using transgenic and knockout hibition of 20-HETE.132 CYP4A and NADPH oxidase expression mouse models, sEH inhibitors, and is upregulated in glomeruli of diabetic EETs analogs have provided unequivocal OVE26 mice. Blockade of 20-HETE de- evidence of the antihypertensive effects CYP450 METABOLITES OF AA creased ROS and ameliorated apoptosis of EETs (Figure 3).2,23,62,63 ANG II– or AND CKD and albuminuria.136 Thus, 20-HETE has L-NAME–induced hypertension is at- been suggested to contribute to diabetic tenuated in transgenic mice expressing 20-HETE nephropathy.138,140–142 Roshanravan human endothelial CYP2J2 or CYP2C8. Decreased levels of renal 20-HETE and et al.143 recently reported that 20-HETE This was associated with increased EETs EETs in Dahl S rats promote sodium increases TRPC6 activity in podocytes levels that enhanced the Af-art response to retention and the development of salt- secondary to activation of ROS produc- acetylcholine and impaired the vasocon- sensitive hypertension. The decrease in tion. Activation of TRPC6 causes foot strictor response to endothelin.127 Simi- 20-HETE also impairs the myogenic and process effacement,144–147 but paradoxi- larly, inhibition or knockout of sEH tubuloglomerular feedback responses of cally, effacement prevents podocyte enhances EETs production and opposes the Af-art, elevates glomerular capillary detachment.148 Thus, the net effects of the development of ANG II, L-NAME, pressure, increases the permeability of 20-HETE activation of the TRPC6 chan- and DOCA salt models of hyperten- the glomerulus to albumin (Palb), and nels in podocytes on the glomerular filtra- sion.64,128–131 Administration of epoxyge- upregulates the expression of TGF-b tion barrier remains to be determined. nase inhibitors or knockout of CYP2C44 leading to the development of protein- is associated with decreased renal EETs, uria and CKD.11,117,133 Normalization of EETs elevated ENaC activity in the CCD, and the 20-HETE levels with fibrates or EETs have antihypertensive properties salt-sensitive hypertension that is re- transfer of wild-type CYP4A genes in and protect against renal and vascular versed by amiloride.67–69 Knockout of congenic Dahl S strains11,115–117,134 pre- injury by reducing inflammation, oxida- CYP4A10 also produces salt-sensitive vented the development of proteinuria tive stress, and endothelial dysfunc- hypertension due to suppression of and renal injury. We hypothesize that tion.1–3,62,63 Exogenous 8, 9 EET has a

2848 Journal of the American Society of Nephrology J Am Soc Nephrol 28: 2845–2855, 2017 www.jasn.org BRIEF REVIEW direct protective effect on the glomeru- HETE levels by transfer of wild-type RAF/MEK/extracellular signal–regulated lus.149 Inhibition or knockout of sEH CYP4A genes on 5 in kinase and PI3K-AKT pathways second- increases the production of EETs and re- SS.5BN consomic or SS.5Lew 4A+ congenic ary to activation of c-Src and the EGFR.171 duces proteinuria, glomerular injury, rats also protected against renal IRI.158 It stimulates the production of ROS and and renal inflammation in animals However, another study indicated that in- inflammatory cytokines.3,28,175,176 Poly- with unilateral urinary obstruction, di- hibition of 20-HETE protects against IRI in cystic kidney disease (PKD) is associated abetic- and obesity-induced nephropa- acutely uninephrectomized rats.159 The with activation of the same pathways. thy, reduced renal mass ANG II, and reason for the contradictory results is un- The production of 20-HETE is increased DOCA-salt hypertension.24,62,63,140,150 certain,butitislikelyrelatedtothedifferent in the kidneys of rodents in PKD Administration of EET agonists or upre- experimental models, because a subsequent models and the sera of patients with gulation of EETs formation in CYP2J2 study157 reported that 20-HETE inhibition PKD.171,177,178 Inhibition of 20-HETE transgenic mice or after administration reduced IRI in uninephrectomized rats but production reduced cyst formation in ro- of a CYP2J2 viral vector reduced pro- had the opposite effect using the bilateral dent models, and this was associated with teinuria, renal inflammation, and glo- ischemic model. diminished activation of the EGFR and merular injury in STZ diabetic or ANG Given the renoprotective and anti- p44/42 mitogen-activated protein kinase II hypertensive mice141,151 and reduced inflammatory effects of EETs, it is sur- and cAMP levels.171,177–179 These studies renal mass rats.152 An orally active ana- prising that there have not been more suggest that 20-HETE may be a potential log prevented the development of glo- studies to examine their effects in models biomarker and therapeutic target for the merular injury and proteinuria in Dahl of AKI. Cisplatin-induced nephrotoxicity treatment of PKD. S rats without altering BP.153 The com- was attenuated in sEH knockout mice,161 mon protective effects of EETs in all of whereas an EET agonist ameliorated cy- these models of CKD are reduced oxida- closporin- and radiation-induced ne- SUMMARY tive stress and inflammation. Thus, sEH phropathy in rats.162,163 More recently, inhibitors and EETs agonists have the effects of EETs on the renal IRI were Sequence variants in the genes that reduce emerged as promising therapeutic tar- examined. The renal EET-to-DiHETE the production of 20-HETE generally are gets for the treatment of CKD. ratio was elevated in sEH knockout associated with the development of hyper- mice, but unexpectedly, plasma creati- tension, whereas the results for those that nine concentration and the degree of alter the production of EETs are inconsis- CYP450 METABOLITES, AKI, AND IRI were greater than in controls.164 tent. Elevations in the formation of RENAL TRANSPLANTATION 20-HETE increase renal and peripheral vas- Transplant cular resistance and produce salt-insensitive AKI Plasma 20-HETE levels increased shortly forms of hypertension resistant to renal Ischemia- (IRI) is the after renal transplantation, and it was a injury, whereas decreases in the formation most common cause of AKI.1,154,155 Re- positive predictorof graft function.165,166 of 20-HETE increase and promote salt- nal 20-HETE production is elevated af- It was suggested to serve as an early bio- sensitive hypertension and renal injury. ter renal ischemia.156–159 20-HETE has marker of allograft function. More re- 20-HETE levels are elevated after renal is- numerous effects on renal tubular and cently, inactivating variants in CYP4F2 chemia and may protect against injury. vascular function that can alter IRI. It and CYP4A11 were associated with de- They are also elevated in PKD. Thus, 20- could prolong vasoconstriction after re- layed graft function and post-transplant di- HETE agonists or antagonists may be perfusion and augment IRI. It increases abetes mellitus.167,168 Similarly, variants in useful for these conditions. EETs have an- oxidative stress and the release of inflam- CYP2C8, CYP2J2, and sEH that reduce tihypertensive and anti-inflammatory matory cytokines and potentiates IRI levels of EETs are associated with allograft properties. Decreases in the formation of in renal epithelial cells.160 However, 20- dysfunction.168–170 These results suggest EETspromote salt-sensitive hypertension. HETE could attenuate IRI by increasing that both 20-HETE and EETs may have a They are renoprotective in models of CKD medullary oxygenation, because it in- protective role in renal transplant. by reducing oxidative stress and inflam- creases medullary blood flow and in- mation. Thus, inhibitors of sEH and orally hibits tubular sodium transport.156,157 active EETs agonists are considered prom- Administration of a 20-HETE agonist CYP450 METABOLITES OF AA ising therapies for hypertension and dia- was found to prevent the secondary fall AND POLYCYSTIC KIDNEY betic nephropathy. in medullary blood flow and medullary DISEASE hypoxia and reduce IRI after bilateral re- nal ischemia.156–159 Similarly, Dahl S 20-HETE promotes ACKNOWLEDGMENTS rats that have a deficiency in renal 20- and proliferation of a variety of cell HETEaremoresusceptibletorenalIRI types.171–174 Its effects on renal epithelial This study was supported by grants AG050049 than other strains. Increasing renal 20- cells are associated with activation of the (to F.F.), P20GM104357 (pilot: to F.F.; cores B

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