Transcriptional regulation of renal cytoprotective genes by Nrf2 and its potential use as a therapeutic target to mitigate cisplatin-induced nephrotoxicity.
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.
Aleksunes
Lauren M
LM
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160-7417, USA.
Goedken
Michael J
MJ
Rockwell
Cheryl E
CE
Thomale
Juergen
J
Manautou
Jose E
JE
Klaassen
Curtis D
CD
D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001806:Blood Urea Nitrogen; D015153:Blotting, Western; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D018736:DNA Adducts / Q000737:chemistry; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000473:pathology; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000235:genetics* / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000819:agonists* / Q000502:physiology*; D009336:Necrosis; D021141:Nucleic Acid Amplification Techniques; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D010984:Platinum / Q000737:chemistry; D012333:RNA, Messenger / Q000096:biosynthesis; D014157:Transcription Factors / Q000378:metabolism
C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D000970:Antineoplastic Agents; D018736:DNA Adducts; D007093:Imidazoles; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; D010984:Platinum; D009828:Oleanolic Acid; D002945:Cisplatin