title: Novel orally active epoxyeicosatrienoic acid (EET) analogs attenuate cisplatin nephrotoxicity.
abstract: Nephrotoxicity severely limits the use of the anticancer drug cisplatin. Oxidative stress, inflammation, and endoplasmic reticulum (ER) stress contribute to cisplatin-induced nephrotoxicity. We developed novel orally active epoxyeicosatrienoic acid (EET) analogs and investigated their prophylactic effect in cisplatin-induced nephrotoxicity in rats. Cisplatin-induced nephrotoxicity was manifested by increases in blood urea nitrogen, plasma creatinine, urinary N-acetyl-β-(d)-glucosaminidase activity, kidney injury molecule 1, and histopathology. EET analogs (10 mg/kg/d) attenuated cisplatin-induced nephrotoxicity by reducing these renal injury markers by 40-80% along with a 50-70% reduction in renal tubular cast formation. This attenuated renal injury is associated with reduced oxidative stress, inflammation, and ER stress evident from reduction in related biomarkers and in the renal expression of genes involved in these pathways. Moreover, we demonstrated that the attenuated nephrotoxicity correlated with decreased apoptosis that is associated with 50-90% reduction in Bcl-2 protein family mediated proapoptotic signaling, reduced renal caspase-12 expression, and a 50% reduction in renal caspase-3 activity. We further demonstrated in vitro that the protective activity of EET analogs does not compromise the anticancer effects of cisplatin. Collectively, our data provide evidence that EET analogs attenuate cisplatin-induced nephrotoxicity by reducing oxidative stress, inflammation, ER stress, and apoptosis without affecting the chemotherapeutic effects of cisplatin.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, Wisconsin 53226, USA.
authors.forename: Md Abdul Hye
authors.initials: MA
authors.lastname: Khan
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Ganesh
authors.initials: G
authors.lastname: Kumar
authors.forename: Stephen X
authors.initials: SX
authors.lastname: Skapek
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: John D
authors.initials: JD
authors.lastname: Imig
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001806:Blood Urea Nitrogen; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D003404:Creatinine / Q000097:blood; D003432:Cross-Linking Reagents / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051381:Rats; D011921:Rats, Inbred WKY; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D003432:Cross-Linking Reagents; D019253:Proto-Oncogene Proteins c-bcl-2; C000606290:SOD1 protein, human; D014665:Vasodilator Agents; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; D003404:Creatinine; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D015126:8,11,14-Eicosatrienoic Acid; D002945:Cisplatin
keywords: acute kidney injury; chemotherapeutics; eicosanoids