title: Novel Omega-3 Fatty Acid Epoxygenase Metabolite Reduces Kidney Fibrosis.
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.
authors.affiliation: Department of Pharmacology &amp; Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. amitsharma@mcw.edu.
authors.forename: Amit
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Pharmacology &amp; Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. abhkhan@mcw.edu.
authors.forename: Md Abdul
authors.initials: MA
authors.lastname: Hye Khan
authors.affiliation: Department of Pharmacology &amp; Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. slevick@mcw.edu.|Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA. slevick@mcw.edu.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Levick
authors.affiliation: Department of Entomology &amp; Cancer Center, University of California, Davis, CA 95616, USA. skslee@ucdavis.edu.
authors.forename: Kin Sing Stephen
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Department of Entomology &amp; Cancer Center, University of California, Davis, CA 95616, USA. bdhammock@ucdavis.edu.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: Department of Pharmacology &amp; Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. jdimig@mcw.edu.
authors.forename: John D
authors.initials: JD
authors.lastname: Imig
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D003094:Collagen / Q000378:metabolism*; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage* / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism*; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D013237:Stereoisomerism
chemical_list: D000199:Actins; D015525:Fatty Acids, Omega-3; D005231:Fatty Acids, Unsaturated; C544013:alpha-smooth muscle actin, mouse; D003094:Collagen; C026219:docosapentaenoic acid; D006909:Hydroxyproline
keywords: epithelial-to-mesenchymal transition; fatty acid epoxide; omega-3 fatty acid; renal fibrosis