Bardoxolone methyl (BARD) ameliorates ischemic AKI and increases expression of protective genes Nrf2, PPARγ, and HO-1

Qing Qing Wu, Yanxia Wang, Martin Senitko, Colin Meyer, W. Christian Wigley, Deborah A. Ferguson, Eric Grossman, Jianlin Chen, Xin J. Zhou, John Hartono, Pamela Winterberg, Bo Chen, Anapam Agarwal, Christopher Y. Lu

Research output: Contribution to journalArticle

110 Citations (Scopus)

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 ischemiareperfusion 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.

Original languageEnglish (US)
Pages (from-to)1180-1192
Number of pages13
JournalAmerican Journal of Physiology - Renal Physiology
Volume300
Issue number5
DOIs
StatePublished - May 2011

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NF-E2-Related Factor 2
Peroxisome Proliferator-Activated Receptors
Heme Oxygenase-1
Acute Kidney Injury
Gene Expression
Leukocytes
Ischemia
methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate
Ligands
Messenger RNA
Proteins
Cisplatin
Reperfusion
Endothelium
Fluorescent Antibody Technique
Half-Life

Keywords

  • Acute kidney injury
  • Cisplatin
  • Heme oxygenase 1
  • Ischemia

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Bardoxolone methyl (BARD) ameliorates ischemic AKI and increases expression of protective genes Nrf2, PPARγ, and HO-1. / Wu, Qing Qing; Wang, Yanxia; Senitko, Martin; Meyer, Colin; Wigley, W. Christian; Ferguson, Deborah A.; Grossman, Eric; Chen, Jianlin; Zhou, Xin J.; Hartono, John; Winterberg, Pamela; Chen, Bo; Agarwal, Anapam; Lu, Christopher Y.

In: American Journal of Physiology - Renal Physiology, Vol. 300, No. 5, 05.2011, p. 1180-1192.

Research output: Contribution to journalArticle

Wu, QQ, Wang, Y, Senitko, M, Meyer, C, Wigley, WC, Ferguson, DA, Grossman, E, Chen, J, Zhou, XJ, Hartono, J, Winterberg, P, Chen, B, Agarwal, A & Lu, CY 2011, 'Bardoxolone methyl (BARD) ameliorates ischemic AKI and increases expression of protective genes Nrf2, PPARγ, and HO-1', American Journal of Physiology - Renal Physiology, vol. 300, no. 5, pp. 1180-1192. https://doi.org/10.1152/ajprenal.00353.2010
Wu, Qing Qing ; Wang, Yanxia ; Senitko, Martin ; Meyer, Colin ; Wigley, W. Christian ; Ferguson, Deborah A. ; Grossman, Eric ; Chen, Jianlin ; Zhou, Xin J. ; Hartono, John ; Winterberg, Pamela ; Chen, Bo ; Agarwal, Anapam ; Lu, Christopher Y. / Bardoxolone methyl (BARD) ameliorates ischemic AKI and increases expression of protective genes Nrf2, PPARγ, and HO-1. In: American Journal of Physiology - Renal Physiology. 2011 ; Vol. 300, No. 5. pp. 1180-1192.
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AU - Meyer, Colin

AU - Wigley, W. Christian

AU - Ferguson, Deborah A.

AU - Grossman, Eric

AU - Chen, Jianlin

AU - Zhou, Xin J.

AU - Hartono, John

AU - Winterberg, Pamela

AU - Chen, Bo

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N2 - 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 ischemiareperfusion 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.

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