title: The epoxyeicosatrienoic acid analog PVPA ameliorates cyclosporine-induced hypertension and renal injury in rats.
abstract: The introduction of calcineurin inhibitors (CNI) into clinical practice in the late 1970s transformed organ transplantation and led to significant improvement in acute rejection episodes. However, despite their significant clinical utility, the use of these agents is hampered by the development of hypertension and nephrotoxicity, which ultimately lead to end-stage kidney disease and overt cardiovascular outcomes. There are currently no effective agents to treat or prevent these complications. Importantly, CNI-free immunosuppressive regimens lack the overall efficacy of CNI-based treatments and put patients at risk of allograft rejection. Cytochrome P-450 epoxygenase metabolites of arachidonic acid, epoxyeicosatrienoic acids (EETs), have potent vasodilator and antihypertensive properties in addition to many cytoprotective effects, but their effects on CNI-induced nephrotoxicity have not been explored. Here, we show that PVPA, a novel, orally active analog of 14,15-EET, effectively prevents the development of hypertension and ameliorates kidney injury in cyclosporine-treated rats. PVPA treatment reduced proteinuria and renal dysfunction induced by cyclosporine. PVPA inhibited inflammatory cell infiltration into the kidney and decreased renal fibrosis. PVPA also reduced tubular epithelial cell apoptosis, attenuated the generation of reactive oxygen species, and modulated the unfolded protein response that is associated with endoplasmic reticulum stress. Consistent with the in vivo data, PVPA attenuated cyclosporine-induced apoptosis of NRK-52E cells in vitro. These data indicate that the cytochrome P-450/EET system offers a novel therapeutic strategy to treat or prevent CNI-induced nephrotoxicity.
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; mmyeboah@mcw.edu.
authors.forename: Michael M
authors.identifier: 0000-0003-0415-6857
authors.initials: MM
authors.lastname: Yeboah
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
authors.forename: Md Abdul
authors.initials: MA
authors.lastname: Hye Khan
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Marla A
authors.initials: MA
authors.lastname: Chesnik
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
authors.forename: Amit
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Mahesh P
authors.initials: MP
authors.lastname: Paudyal
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
authors.forename: John D
authors.initials: JD
authors.lastname: Imig
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001095:Arachidonic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D016572:Cyclosporine; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D007166:Immunosuppressive Agents; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D011507:Proteinuria / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001095:Arachidonic Acids; D007166:Immunosuppressive Agents; D016572:Cyclosporine
keywords: cyclosporine; epoxyeicosatrienoic acids; hypertension; nephrotoxicity; transplantation