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Cited by 60Genomics, phytochemicals, and oxidative stressAcute Kidney Injury ResearchHeavy Metal Exposure and Toxicity

Coordinated induction of Nrf2 target genes protects against iron nitrilotriacetate (FeNTA)-induced nephrotoxicity

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TANAKA, Y, ALEKSUNES, L, GOEDKEN, M, CHEN, C, REISMAN, S, MANAUTOU, J, KLAASSEN, C·2008·Toxicology and Applied Pharmacology
DOI 10.1016/j.taap.2008.05.022PMC PMC2582522
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Abstract

The iron chelate, ferric nitrilotriacetate (FeNTA), induces acute proximal tubular necrosis as a consequence of lipid peroxidation and oxidative tissue damage. Chronic exposure of FeNTA leads to a high incidence of renal adenocarcinomas in rodents. NF-E2-related factor 2 (Nrf2) is a transcription factor that is activated by oxidative stress and electrophiles, and regulates the basal and inducible expression of numerous detoxifying and antioxidant genes. To determine the roles of Nrf2 in regulating renal gene expression and protecting against oxidative stress-induced kidney damage, wild-type and Nrf2-null mice were administered FeNTA. Renal Nrf2 protein translocated to the nucleus at 6h after FeNTA treatment. FeNTA increased mRNA levels of Nrf2 target genes, including NQO1, GCLC, GSTpi1/2, Mrp1, 2, and 4 in kidneys from wild-type mice, but not Nrf2-null mice. Protein expression of NQO1, a prototypical Nrf2 target gene, was increased in wild-type mice, with no change in Nrf2-null mice. FeNTA produced more nephrotoxicity in Nrf2-null mice than wild-type mice as indicated by higher serum urea nitrogen and creatinine levels, as more urinary NAG, stronger 4-hydroxynonenal protein adduct staining, and more extensive proximal tubule damage. Furthermore, pretreatment with CDDO-Im, a potent small molecule Nrf2 activator, protected mice against FeNTA-induced renal toxicity. Collectively, these results suggest that activation of Nrf2 protects mouse kidneys from FeNTA-induced oxidative stress damage by coordinately up-regulating the expression of cytoprotective genes.

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Crossref · 10.1016/j.taap.2008.05.022

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  • Nrf2 plays a prominent role in kidney function.

    “Because targeting of Keap1 with CDDO-Me can induce nuclear factor erythroid 2–related factor 2, which plays a prominent role in kidney function (Tanaka et al., 2008), it has been evaluated in Phase I/II trials for clinical activity in patients with moderate to severe chronic kidney disease.”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Tanaka et al., 2008

    The Discussion (page not provided) concludes that Nrf2 target-gene induction protects kidneys from FeNTA-induced oxidative damage. That supports an important role in renal protection, but the paper does not establish the broader claim that Nrf2 plays a prominent role in kidney function generally. (LLM, conf=0.84)

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Authors
TANAKA, Y., ALEKSUNES, L., GOEDKEN, M., CHEN, C., REISMAN, S., MANAUTOU, J., & KLAASSEN, C.
Affiliations
  • University of Kansas Medical Center (US)
  • University of Connecticut (US)
Corresponding author
KLAASSEN, C
ORCID
Venue
Toxicology and Applied Pharmacology
Publisher
Elsevier BV
Published
2008-09-15
Volume
231
Issue
3
Pages
364-373
ISSN
0041-008X (ISSN-L)
DOI
10.1016/j.taap.2008.05.022
PMC
PMC2582522
OpenAlex
W2064994854
Cited by
60
References
0
Citations by year
2025: 2 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 6 · 2018: 4 · 2017: 2 · 2016: 3 · 2015: 7 · 2014: 4 · 2013: 7 · 2012: 4
FWCI
1.78
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Toxicology and Applied Pharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Rutgers University Community Repository (Rutgers University) (submittedVersion)
Funders
  • Dartmouth College
  • National Institutes of Health
  • University of California, Irvine
  • National Institute of Environmental Health Sciences (ES 09716, ES 09649, ES-07079, R01ES009649, T32ES007079, R01ES009716)
  • National Center for Research Resources (RR021940, P20RR021940)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Heavy Metal Exposure and Toxicity
Keywords
Nrf2, ferric nitrilotriacetate, nephrotoxicity, oxidative stress, renal protection, NQO1, glutathione S-transferase, MRP transporters, CDDO-Im, Nrf2 activators, proximal tubular necrosis, lipid peroxidation, 4-hydroxynonenal, renal cell carcinoma
MeSH terms
Animals, Dose-Response Relationship, Drug, Ferric Compounds, Gene Expression Regulation, Kidney Diseases, Male, Mice, Inbred C57BL, Nitrilotriacetic Acid, Oxidative Stress, NF-E2-Related Factor 2, Mice

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