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Novel Omega-3 Fatty Acid Epoxygenase Metabolite Reduces Kidney Fibrosis

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Novel Omega-3 Fatty Acid Epoxygenase Metabolite Reduces Kidney Fibrosis UC Davis UC Davis Previously Published Works Title Novel Omega-3 Fatty Acid Epoxygenase Metabolite Reduces Kidney Fibrosis. Permalink https://escholarship.org/uc/item/0sk9110v Journal International journal of molecular sciences, 17(5) ISSN 1422-0067 Authors Sharma, Amit Hye Khan, Md Abdul Levick, Scott P et al. Publication Date 2016-05-18 DOI 10.3390/ijms17050751 Peer reviewed eScholarship.org Powered by the California Digital Library University of California International Journal of Molecular Sciences Article Novel Omega-3 Fatty Acid Epoxygenase Metabolite Reduces Kidney Fibrosis Amit Sharma 1,†, Md. Abdul Hye Khan 1,†, Scott P. Levick 1,2, Kin Sing Stephen Lee 3, Bruce D. Hammock 3 and John D. Imig 1,* 1 Department of Pharmacology & Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; [email protected] (A.S.); [email protected] (M.A.H.K.); [email protected] (S.P.L.) 2 Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA 3 Department of Entomology & Cancer Center, University of California, Davis, CA 95616, USA; [email protected] (K.S.S.L.); [email protected] (B.D.H.) * Correspondence: [email protected]; Tel.: +1-414-955-4785; Fax: +1-414-955-6545 † These authors contributed equally to this work. Academic Editor: Alan Parrish Received: 12 April 2016; Accepted: 9 May 2016; Published: 18 May 2016 Abstract: Cytochrome P450 (CYP) monooxygenases epoxidize the omega-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid into novel epoxydocosapentaenoic acids (EDPs) that have multiple biological actions. The present study determined the ability of the most abundant EDP regioisomer, 19,20-EDP to reduce kidney injury in an experimental unilateral ureteral obstruction (UUO) renal fibrosis mouse model. Mice with UUO developed kidney tubular injury and interstitial fibrosis. UUO mice had elevated kidney hydroxyproline content and five-times greater collagen positive fibrotic area than sham control mice. 19,20-EDP treatment to UUO mice for 10 days reduced renal fibrosis with a 40%–50% reduction in collagen positive area and hydroxyproline content. There was a six-fold increase in kidney α-smooth muscle actin (α-SMA) positive area in UUO mice compared to sham control mice, and 19,20-EDP treatment to UUO mice decreased α-SMA immunopositive area by 60%. UUO mice demonstrated renal epithelial-to-mesenchymal transition (EMT) with reduced expression of the epithelial marker E-cadherin and elevated expression of multiple mesenchymal markers (FSP-1, α-SMA, and desmin). Interestingly, 19,20-EDP treatment reduced renal EMT in UUO by decreasing mesenchymal and increasing epithelial marker expression. Overall, we demonstrate that a novel omega-3 fatty acid metabolite 19,20-EDP, prevents UUO-induced renal fibrosis in mice by reducing renal EMT. Keywords: omega-3 fatty acid; fatty acid epoxide; renal fibrosis; epithelial-to-mesenchymal transition 1. Introduction Chronic kidney disease (CKD) is a progressive disease that results in end-stage renal disease, and there is a need for renal replacement therapy or transplantation. Indeed, CKD is rapidly increasing in industrialized countries due to increases in disorders, such as obesity, and CKD is a major economic healthcare burden [1–3]. Tubulointerstitial fibrosis is an early event in progressive renal disease that leads to functional abnormalities and eventual decline of renal function irrespective of the contributions of diverse pathophysiological factors [4–6]. Proximal tubular epithelial cells play a central role in renal tubulointerstitial fibrosis [7]. Accumulation of extracellular matrix components and loss of tubular architecture are key features of tubulointerstitial fibrosis. Epithelial mesenchymal transition (EMT) occurs at a critical period in the pathogenesis of tubulointerstitial fibrosis and involves Int. J. Mol. Sci. 2016, 17, 751; doi:10.3390/ijms17050751 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2016, 17, 751 2 of 11 renal tubular epithelial cells transforming phenotypically and functionally into myofibroblasts [8]. α ThisInt. transformation J. Mol. Sci. 2016, 17, is751 characterized by a decline in E-cadherin expression and an elevation in2 of 10-smooth muscle actin (α-SMA) expression. Therefore, EMT in the kidneys offers a significant therapeutic target, andepithelial emphasizes cells thetransforming need to develop phenotypically approaches and to functionally inhibit tubular into epithelial myofibroblasts cells from [8]. undergoingThis EMTtransformation to prevent tubulointerstitial is characterized by fibrosis. a decline in E-cadherin expression and an elevation in α-smooth muscleOne suchactin novel(α-SMA) approach expression. could Therefore, be the metabolites EMT in the of kidneys cytochrome offers P450 a significant (CYP450) therapeutic monooxygenase target, and emphasizes the need to develop approaches to inhibit tubular epithelial cells from pathway that represent the third branch of polyunsaturated fatty acid (PUFA) metabolism [9]. undergoing EMT to prevent tubulointerstitial fibrosis. CYP450 monooxygenases can epoxidize PUFAs to generate three-membered oxirane known as One such novel approach could be the metabolites of cytochrome P450 (CYP450) epoxidesmonooxygenase [9]. In the pathway case of that arachidonic represent acid, the third CYP450 branch monooxygenases of polyunsaturated convert fatty thisacid omega-6 (PUFA) PUFA intometabolism epoxyeicosatrienoic [9]. CYP450 acids monooxygenases (EETs), which can act toepoxidize regulatecardiovascular PUFAs to generate function three-membered and inflammatory processesoxirane toknown protect as epoxides the kidney [9]. inIn athe number case of ofarachidonic pathologies acid, [10 CYP450]. In addition monooxygenases to omega-6 convert PUFA, this CYP450 monooxygenasesomega-6 PUFA into also epoxyeicosatrienoic converts the omega-3 acids PUFA (EETs) eicosapentaenoic, which act to regulatecardiovascular acid (EPA) and docosahexaenoic function acidand (DHA) inflammatory into novel processes epoxyeicosatetraenoic to protect the kidney (EEQs) in a number and epoxydocosapentaenoicof pathologies [10]. In addition (EDPs) to acids, respectivelyomega-6 PUFA, [11,12 CYP450]. Recent monooxygenases studies demonstrated also converts anti-hypertensive the omega-3 PUFA and eicosapentaenoic anti-inflammatory acid actions of 19,20-EDP,(EPA) and anddocosahexaenoic indicated 19,20-EDP acid (DHA) as a novel into CYP450 novel metaboliteepoxyeicosatetraenoic with promising (EEQs) cardiovascular and epoxydocosapentaenoic (EDPs) acids, respectively [11,12]. Recent studies demonstrated actions [13,14]. anti-hypertensive and anti-inflammatory actions of 19,20-EDP, and indicated 19,20-EDP as a novel In the present study, we examined the kidney protective and anti-fibrotic action of 19,20-EDP CYP450 metabolite with promising cardiovascular actions [13,14]. in unilateralIn the present ureteral study, obstruction we examined (UUO), the kidney a model prot forective renal and tubulointerstitial anti-fibrotic action fibrosis.of 19,20-EDP Our in results demonstratedunilateral ureteral marked obstruction kidney protection (UUO), a and model anti-fibrotic for renal actions tubulointerstitial of 19,20-EDP fibrosis. in UUO Our model. results We also demonstrateddemonstrated that marked the anti-fibrotickidney protection action and of anti-fibr 19,20-EDPotic actions is caused of 19,20-EDP by its ability in UUO to model. reduce We renal also EMT. demonstrated that the anti-fibrotic action of 19,20-EDP is caused by its ability to reduce renal EMT. 2. Results 2. Results 2.1. 19,20-EDP Treatment Attenuates UUO Renal Injury 2.1. 19,20-EDP Treatment Attenuates UUO Renal Injury UUO mice developed renal dysfunction with elevated BUN (51 ˘ 3 mg/dL) compared to sham controlUUO mice (30mice˘ developed3 mg/dL). renal The dysfunction CYP450 epoxygenase with elevated metabolite BUN (51 of± 3 docosahexaenoic mg/dL) compared acid, to sham 19,20-EDP markedlycontrol reducedmice (30 the± 3 bloodmg/dL). urea The nitrogen CYP450 (BUN) epoxygenase level in metabolite UUO mice of (33 docosahexaenoic˘ 3 mg/dL) and acid, reduced 19,20-EDP markedly reduced the blood urea nitrogen (BUN) level in UUO mice (33 ± 3 mg/dL) and it to a level similar to sham control mice (Figure1A). Serum creatinine level was elevated in vehicle reduced it to a level similar to sham control mice (Figure 1A). Serum creatinine level was elevated in treated UUO (1.3 ˘ 0.1 mg/dL) compared to sham-control (0.6 ˘ 0.09 mg/dL) mice. EDP treatment vehicle treated UUO (1.3 ± 0.1 mg/dL) compared to sham-control (0.6 ± 0.09 mg/dL) mice. EDP reducedtreatment serum reduced creatinine serum in creatinine UUO mice in (0.9UUO˘ mice0.09 mg/dL).(0.9 ± 0.09 UUO mg/dL). mice UUO also mice developed also developed tubular injury withtubular marked injury tubular with atrophymarked tubular and 5-times atrophy higher and amount5-times higher of tubular amount cast of formation tubular cast compared formation to sham control.compared Treatment to sham ofcontrol. 19,20-EDP Treatment reduced of 19,20-ED renalP tubular reduced injury renal intubular the UUOinjury micein the and UUO also mice reduced tubularand also cast reduced formation tubular by 50%cast formation (Figure1B,C). by 50% (Figure 1B,C). Figure 1. 19,20-EDP treatment improved kidney function and reduced renal tubular injury in Figure 1. 19,20-EDP treatment improved kidney function and reduced renal tubular injury in UUO by UUO by reducing blood urea nitrogen (A) and, tubular cast formation (B); representative reducing blood urea
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