title: Bardoxolone methyl (BARD) ameliorates ischemic AKI and increases expression of protective genes Nrf2, PPARγ, and HO-1.
abstract: Ischemic acute kidney injury (AKI) triggers expression of adaptive (protective) and maladaptive genes. Agents that increase expression of protective genes should provide a therapeutic benefit. We now report that bardoxolone methyl (BARD) ameliorates ischemic murine AKI as assessed by both renal function and pathology. BARD may exert its beneficial effect by increasing expression of genes previously shown to protect against ischemic AKI, NF-E2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor-γ (PPARγ), and heme oxygenase 1 (HO-1). Although we found that BARD alone or ischemia-reperfusion alone increased expression of these genes, the greatest increase occurred after the combination of both ischemia-reperfusion and BARD. BARD had a different mode of action than other agents that regulate PPARγ and Nrf2. Thus we report that BARD regulates PPARγ, not by acting as a ligand but by increasing the amount of PPARγ mRNA and protein. This should increase ligand-independent effects of PPARγ. Similarly, BARD increased Nrf2 mRNA; this increased Nrf2 protein by mechanisms in addition to the prolongation of Nrf2 protein half-life previously reported. Finally, we localized expression of these protective genes after ischemia and BARD treatment. Using double-immunofluorescence staining for CD31 and Nrf2 or PPARγ, we found increased Nrf2 and PPARγ on glomerular endothelia in the cortex; Nrf2 was also present on cortical peritubular capillaries. In contrast, HO-1 was localized to different cells, i.e., tubules and interstitial leukocytes. Although Nrf2-dependent increases in HO-1 have been described, our data suggest that BARD's effects on tubular and leukocyte HO-1 during ischemic AKI may be Nrf2 independent. We also found that BARD ameliorated cisplatin nephrotoxicity.
authors.affiliation: Department of Internal Medicine, Nephrology Division, UT Southwestern Medical Center, Dallas, TX 75390-8856, USA.
authors.forename: Qing Qing
authors.initials: QQ
authors.lastname: Wu
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Wang
authors.forename: Martin
authors.initials: M
authors.lastname: Senitko
authors.forename: Colin
authors.initials: C
authors.lastname: Meyer
authors.forename: W Christian
authors.initials: WC
authors.lastname: Wigley
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Ferguson
authors.forename: Eric
authors.initials: E
authors.lastname: Grossman
authors.forename: Jianlin
authors.initials: J
authors.lastname: Chen
authors.forename: Xin J
authors.initials: XJ
authors.lastname: Zhou
authors.forename: John
authors.initials: J
authors.lastname: Hartono
authors.forename: Pamela
authors.initials: P
authors.lastname: Winterberg
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.forename: Anapam
authors.initials: A
authors.lastname: Agarwal
authors.forename: Christopher Y
authors.initials: CY
authors.lastname: Lu
mesh_terms: D058186:Acute Kidney Injury / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D000704:Analysis of Variance; D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000201:enzymology; D002945:Cisplatin; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D007511:Ischemia / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D047495:PPAR gamma; D012333:RNA, Messenger; D009828:Oleanolic Acid; C445068:bardoxolone methyl; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D002945:Cisplatin