Bardoxolone methyl (BARD) ameliorates ischemic AKI and increases expression of protective genes Nrf2, PPARγ, and HO-1
Open Access
- 1 May 2011
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Renal Physiology
- Vol. 300 (5), F1180-F1192
- https://doi.org/10.1152/ajprenal.00353.2010
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.Keywords
This publication has 71 references indexed in Scilit:
- Transcriptional Regulation of Renal Cytoprotective Genes by Nrf2 and Its Potential Use as a Therapeutic Target to Mitigate Cisplatin-Induced NephrotoxicityJournal of Pharmacology and Experimental Therapeutics, 2010
- Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studiesNature Biotechnology, 2010
- Human haem oxygenase-1 induction by nitro-linoleic acid is mediated by cAMP, AP-1 and E-box response element interactionsBiochemical Journal, 2009
- The Nrf2-Antioxidant Response Element Signaling Pathway and Its Activation by Oxidative StressJournal of Biological Chemistry, 2009
- Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated miceCarcinogenesis: Integrative Cancer Research, 2009
- Heme oxygenase-1, a critical arbitrator of cell death pathways in lung injury and diseaseFree Radical Biology & Medicine, 2009
- PPARγ and its ligands: therapeutic implications in cardiovascular diseaseClinical Science, 2009
- Coordination of inflammation and metabolism by PPAR and LXR nuclear receptorsCurrent Opinion in Genetics & Development, 2008
- The risk of acute renal failure in patients with chronic kidney diseaseKidney International, 2008
- Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancerNature Reviews Cancer, 2007