Abstract
The use of the chemotherapeutic drug cisplatin is limited in part by nephrotoxicity. Cisplatin causes renal DNA adducts and oxidative stress in rodents. The transcription factor Nrf2 (nuclear factor E2-related factor 2) induces expression of cytoprotective genes, including Nqo1 (NADPH:quinone oxidoreductase 1), Ho-1 (heme oxygenase-1), and Gclc (glutamate cysteine ligase catalytic subunit), in response to electrophilic and oxidative stress. In the present study, plasma and kidneys from wild-type and Nrf2-null mice were collected after receiving cisplatin for evaluation of renal injury, inflammation, mRNA, and protein expression. Compared with wild types, more extensive nephrotoxicity was observed in Nrf2-null mice after cisplatin treatment. Kidneys from Nrf2-null mice treated with cisplatin had more neutrophil infiltration accompanied by increased p65 nuclear factor κB binding and elevated inflammatory mediator mRNA levels. Cisplatin increased renal mRNA and protein expression of cytoprotective genes (Nqo1, Ho-1, Gclc) and transporters Mrp2 and Mrp4 in wild-type but not in Nrf2-null mice. Lastly, the Nrf2 activator, CDDO-Im [2-cyano-3,12-dioxooleana-1,9-dien-28-oic imidazolide], increased Nrf2 signaling in kidneys from wild-type mice and protected them from cisplatin toxicity. Collectively, these data indicate that the absence of Nrf2 exacerbates cisplatin renal damage and that pharmacological activation of Nrf2 may represent a novel therapy to prevent kidney injury. Coordinated regulation of detoxification enzymes and drug transporters and suppression of inflammation by Nrf2 during cisplatin nephrotoxicity are probable defense mechanisms to eliminate toxic mediators and promote proximal tubule recovery.
Footnotes
This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grants DK080774, DK081461]; the National Institutes of Health National Institute of Environmental Health Sciences [Grants ES009649, ES009716, ES007079, ES013714]; and the National Institutes of Health National Center for Research Resources [Grant RR021940].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.170084.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- Nrf2
- nuclear factor erythroid 2-related factor 2
- CDDO-Im
- 2-cyano-3,12-dioxooleana-1,9-dien-28-oic imidazolide
- ARE
- antioxidant-response element
- Mrp(s)
- multidrug resistance-associated protein(s)
- Ho-1
- heme oxygenase-1
- Nqo1
- NADPH:quinone oxidoreductase 1
- PCNA
- proliferating cell nuclear antigen
- Mdr1b
- multidrug resistance protein 1b
- Kim-1
- kidney injury molecule-1
- Topo2a
- topoisomerase 2a
- Gclc
- glutamate cysteine ligase, catalytic subunit
- TUNEL
- terminal deoxynucleotidyl transferase dUTP nick-end labeling
- NFκB
- nuclear factor κB
- Oct2
- organic cation transporter 2
- IL
- interleukin
- ELISA
- enzyme-linked immunosorbent assay
- bp
- base pair.
- Received May 5, 2010.
- Accepted July 2, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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