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

• Published in: Toxicology and applied pharmacology Vol. 231; no. 3; pp. 364 - 373
• Main Authors: Tanaka, Yuji, Aleksunes, Lauren M., Goedken, Michael J., Chen, Chuan, Reisman, Scott A., Manautou, José E., Klaassen, Curtis D.
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 15-09-2008; Elsevier
• Subjects: 1-[2-cyano-3-,12-dioxooleana-1,9-dien-28-oyl]imidazole; 2,6-dichlorophenolindophenol; 4-HNE; 4-hydroxynonenal; 60 APPLIED LIFE SCIENCES; Animals; bDNA; BENZOQUINONES; Biological and medical sciences; branched DNA signal amplification; CARCINOMAS; CDDO-Im; Chemical and industrial products toxicology. Toxic occupational diseases; CREATININE; CYSTEINE; DCPIP; Dose-Response Relationship, Drug; ECR HEATING; FeNTA; Ferric Compounds - toxicity; ferric nitrilotriacetate; GCLC; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; glutamate cysteine ligase catalytic subunit; GLUTATHIONE; glutathione-S-transferase; GST; HEME; heme oxygenase-1; HO-1; IRON; Keap1; Kelch-like ECH-associated protein 1; Kidney; Kidney Diseases - chemically induced; Kidney Diseases - metabolism; Kidney Diseases - prevention & control; LIGASES; Male; Medical sciences; Metals and various inorganic compounds; MICE; Mice, Inbred C57BL; Mrp; Multidrug resistance-associated protein; NAD(P)H:quinone oxidoreductase 1; NF-E2-related factor 2; NF-E2-Related Factor 2 - biosynthesis; NF-E2-Related Factor 2 - genetics; Nitrilotriacetic Acid - analogs & derivatives; Nitrilotriacetic Acid - toxicity; NQO1; Nrf2; OXIDATION; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - physiology; OXYGENASES; relative light units; RLU; TOXICITY; Toxicology; TRANSCRIPTION FACTORS; TUBULES; UREA; NQO1; Oxidative stress; DCPIP; CDDO-Im; GST; HO-1; Mrp; Kidney; GCLC; 4-HNE; FeNTA; Nrf2; bDNA; Keap1; RLU; Kidney disease; Urinary system disease; Targeting; Multidrug resistance related protein; Enzyme; Toxicity; Transition metal; Iron; Prevention; Target; NADPH dehydrogenase (quinone); Urinary system; Gene; Genetics; Oxidoreductases
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2008.05.022

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.