title: The synthetic triterpenoid RTA dh404 (CDDO-dhTFEA) restores endothelial function impaired by reduced Nrf2 activity in chronic kidney disease.
abstract: Chronic kidney disease (CKD) is associated with endothelial dysfunction and accelerated cardiovascular disease, which are largely driven by systemic oxidative stress and inflammation. Oxidative stress and inflammation in CKD are associated with and, in part, due to impaired activity of the cytoprotective transcription factor Nrf2. RTA dh404 is a synthetic oleanane triterpenoid compound which potently activates Nrf2 and inhibits the pro-inflammatory transcription factor NF-κB. This study was designed to test the effects of RTA dh404 on endothelial function, inflammation, and the Nrf2-mediated antioxidative system in the aorta of rats with CKD induced by 5/6 nephrectomy. Sham-operated rats served as controls. Subgroups of CKD rats were treated orally with RTA dh404 (2 mg/kg/day) or vehicle for 12 weeks. The aortic rings from untreated CKD rats exhibited a significant reduction in the acetylcholine-induced relaxation response which was restored by RTA dh404 administration. Impaired endothelial function in the untreated CKD rats was accompanied by significant reduction of Nrf2 activity (nuclear translocation) and expression of its cytoprotective target genes, as well as accumulation of nitrotyrosine and upregulation of NAD(P)H oxidases, 12-lipoxygenase, MCP-1, and angiotensin II receptors in the aorta. These abnormalities were ameliorated by RTA dh404 administration, as demonstrated by the full or partial restoration of the expression of all the above analytes to sham control levels. Collectively, the data demonstrate that endothelial dysfunction in rats with CKD induced by 5/6 nephrectomy is associated with impaired Nrf2 activity in arterial tissue, which can be reversed with long term administration of RTA dh404.
authors.affiliation: Division of Nephrology and Hypertension, Schools of Medicine and Biological Science, University of California-Irvine, 101 The City Drive, City Tower, Suite 400, Orange, CA 92868, USA.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Aminzadeh
authors.affiliation: Reata Pharmaceuticals, Inc., 2801 Gateway Dr. Ste 150, Irving, TX 75063, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Reisman
authors.affiliation: Division of Nephrology and Hypertension, Schools of Medicine and Biological Science, University of California-Irvine, 101 The City Drive, City Tower, Suite 400, Orange, CA 92868, USA.
authors.forename: Nosratola D
authors.initials: ND
authors.lastname: Vaziri
authors.affiliation: Division of Nephrology and Hypertension, Schools of Medicine and Biological Science, University of California-Irvine, 101 The City Drive, City Tower, Suite 400, Orange, CA 92868, USA.
authors.forename: Stan
authors.initials: S
authors.lastname: Shelkovnikov
authors.affiliation: Division of Nephrology and Hypertension, Schools of Medicine and Biological Science, University of California-Irvine, 101 The City Drive, City Tower, Suite 400, Orange, CA 92868, USA.
authors.forename: Seyed H
authors.initials: SH
authors.lastname: Farzaneh
authors.affiliation: Division of Nephrology and Hypertension, Schools of Medicine and Biological Science, University of California-Irvine, 101 The City Drive, City Tower, Suite 400, Orange, CA 92868, USA.
authors.forename: Mahyar
authors.initials: M
authors.lastname: Khazaeli
authors.affiliation: Reata Pharmaceuticals, Inc., 2801 Gateway Dr. Ste 150, Irving, TX 75063, USA.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Meyer
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009392:Nephrectomy; D009828:Oleanolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*
chemical_list: D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; C547749:dh404 compound; D009828:Oleanolic Acid
keywords: 12-LO, 12-lipoxygenase; AT1, angiotensin II receptor type 1; Aorta; Bardoxolone methyl; CDDO-dhTFEA, CDDO-9,11-dihydro-trifluoroethyl amide; CKD, chronic kidney disease; Chronic kidney disease; GAPDH, glyceraldehyde 3-phosphate dehydrogenase, Ho-1, heme oxygenase-1; IKKβ, IkappB kinase β; Inflammation; Keap1, Kelch like ECH-associated protein 1 MCP-1, monocyte chemoattractant protein-1; NAD(P)H, nicotinamide adenine dinucleotide (phosphate), reduced form; NF-κB, nuclear factor κ-light chain-enhancer of activated B cells; NO, nitric oxide; NOS, nitric oxide synthase; NT, nitrotyrosine; Nrf2; Nrf2, nuclear factor erythroid 2-related factor 2; Oxidative stress; PhE, phenylephrine, Rac1, Ras-related C3 botulinum toxin substrate 1; ROS, reactive oxygen species; Sod2, superoxide dismutase 2; Synthetic triterpenoid