Unknown,Transcriptomics,Genomics,Proteomics

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Transcriptomic approach to renal toxicity for cisplatin treatment in Nrf2 WT/KO

ABSTRACT: NF-E2-related factor 2 (Nrf2), a transcription factor activated by oxidative stress, induces phase II conjugating or antioxidant enzymes. In the present study, we examined the effect of Nrf2 knockout (Nrf2 KO) on the kidney injury induced by cisplatin using cDNA microarray analyses. A transcriptomic approach enabled us to extract gene clusters which show significantly different mRNA expression patterns between wild type (WT) and Nrf2 KO mice. In the experimental set, WT vehicle (WT-Veh) and WT cisplatin (WT-Cis) groups were included in our previous GEO database (GSE35257) because the two groups were simultaneously shared with Nrf2 KO vehicle (Nrf2 KO-Veh) and Nrf2 KO cisplatin (Nrf2 KO-Cis) groups in the current report. Copyright (c) 2012 by Korea Food & Drug Administration. WT and Nrf2 KO C57BL/6 mice (9 weeks old, male) were intraperitoneally injected with vehicle (saline) or a single dose of cisplatin (15 mg/kg body weight). The cDNA microarray experiments were done for the kidney of mice 3 days after treatment. Three animals were used per group. WT-Veh and WT-Cis groups were already deposited in GSE35257.

ORGANISM(S): Mus musculus

SUBMITTER: Sang Geon Kim

PROVIDER: E-GEOD-48879 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Clinical use of a major cancer chemotherapeutic agent, cisplatin, is restricted to dose-limiting renal toxicity. A transcriptomic approach enabled us to extract putative molecules including Pleckstrin homology-like domain, family A, member-3 (Phlda3) contributing to the renal injury. This study investigated the expression of Phlda3 and its regulatory role in tubular injury induced by cisplatin in vivo and in vitro. Real-time PCR and immunoblot assays confirmed that Phlda3 was highly up-regulated in the kidney of mice after a single dose of cisplatin treatment, which preceded increases in the blood urea nitrogen or serum creatinine levels. Particularly, the level of Phlda3 transcript was substantially increased at an early time than that of kidney injury molecule-1, and remained elevated. The effect of cisplatin or acetaminophen treatment on Phlda3 expression in the liver was minimal. Consistently, treatment of NRK52E, a renal tubular cell line, with cisplatin caused increases in Phlda3 mRNA and protein. Knockdown of Phlda3 reversed the decrease in cell viability by cisplatin, supporting the role of Phlda3 in cell death. Akt phosphorylation initially increased after cisplatin treatment, but decreased thereafter. Cisplatin treatment elicited p53 accumulation via mdm2 repression, inducing its target genes, p21 and cyclin G1. Phlda3 deficiency attenuated a decrease in Akt phosphorylation by cisplatin, and prevented p53 accumulation, supporting the role of Phlda3 for p53-mediated tubular cell death. Other renal toxicants, cyclosporine A and CdCl2, also enhanced Phlda3-dependent cell death. Overall, nephrotoxicants including cisplatin induce Phlda3, which leads to p53-mediated tubular cell death via mdm2 repression caused by Akt inhibition. Since the datasets reported on the effect of cisplatin on the kidney were obtained from animals treated with multiple and relatively high doses of cisplatin, we did our cDNA array analyses day 3 after a single dose of cisplatin administration to mice (i.p., 15 mg/kg) and compared the profiles of kidney microarray data. The transcriptomic approach enabled us to find the putative genes encoding molecules contributing to renal injury. Among those genes represented on the microarray, 33 genes were found to be differentially expressed by cisplatin treatment when a 2-fold change cutoff was used. The regulation of exemplary mRNAs identified in the array analysis was confirmed by qRT-PCR. C57BL/6 mice (9 weeks old) were intraperitoneally injected with a single dose of cisplatin (15 mg/kg body weight) or vehicle (saline). The cDNA microarray experiments were done for the kidney of mice 3 days after treatment. Each group contained 3 males.

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Transcriptomic approach to renal toxicity for cisplatin treatment in Nrf2 WT/KO

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