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Association of expression of GADD family genes and apoptosis in human kidney proximal tubular (HK-2) cells exposed to nephrotoxic drugs

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Abstract

Background

Nephrotoxicity is often referred to as a side effect of most drugs, but methods for effectively detecting nephrotoxicants still require development.

Objective

In this study, we identified the characteristic cellular responses and target genes affected by three nephrotoxic drugs (cisplatin, amphotericin B, and geneticin) using human oligonucleotide microarray and applied these genes to nephrotoxicity assessment in human kidney proximal tubular cells (HK-2).

Results

Through analysis of the gene expression profiles, it was identified 21 up- and 58 down-regulated genes changed by all three nephrotoxicants. Especially, the nephrotoxicants induced an increase in expression of a family of growth arrest and DNA-damage (GADD)-inducible genes (GADD34, GADD45A, GADD45G, and GADD153). In addition, these nephrotoxicants induced phosphorylation of p38 MAPK, which acts upstream of the GADD-related apoptosis pathway. The influence of other types of nephrotoxicants on expression of GADD family genes was also examined.

Conclusion

Our findings support that cisplatin, amphotericin B, and geneticin mediate induction of the GADD family of genes via the p38 MAPK pathway, resulting in the induction of apoptosis in HK-2 cells. We suggest that the apoptosis-related genes GADD45A and GADD153 may be reasonable candidate biomarkers for the screening of nephrotoxicity of drugs.

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Acknowledgements

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education [NRF-2017R1A6A1A06015181] to Kim Y-.J. and by the “KIST Program” to Ryu, J. C. of the Republic of Korea.

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Author notes

  1. Young-Eun Choi and Mi-Soon Kim have contributed equally to this work.

Authors and Affiliations

  1. Department of Marine Sciences, Incheon National University, 119 Academy-ro, Yeonsu-gu, Incheon, 22012, Republic of Korea

    Young-Eun Choi, Yuna Ha, Jang Kyun Kim, Jae-Sung Rhee & Youn-Jung Kim

  2. Research Institute of Basic Sciences, Incheon National University, 119 Academy-ro, Yeonsu-gu, Incheon, 22012, Republic of Korea

    Young-Eun Choi, Yuna Ha, Jang Kyun Kim, Jae-Sung Rhee & Youn-Jung Kim

  3. in Vitro Pharmacology Group, 1ST Biotherapeutics, Inc. 240 Pangyoyeok-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13493, Republic of Korea

    Mi-Soon Kim

  4. Cellular and Molecular Toxicology Laboratory, Center for Environment, Health and Welfare Research, Korea Institute of Science and Technology (KIST), Cheongryang, P.O. Box 131, Seoul, 02792, Republic of Korea

    Yoon Cho & Jae-Chun Ryu

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Contributions

Conceptualization, JCR and YJK.; methodology, MSK, JSR, and YJK; software, JSR and YC; validation, JKK, MSK, YH, and YEC; writing original draft preparation, MSK and YEC; writing review and editing, JKK, YH, and YJK; visualization, YEC and YC; supervision, JCR and YJK; project administration, JCR and YJK; funding acquisition, JCR and YJK All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Jae-Chun Ryu or Youn-Jung Kim.

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Conflicts of interest

Young-Eun Choi, Mi-Soon Kim, Yuna Ha, Yoon Cho, Jang Kyun Kim, Jae-Sung Rhee, Jae-Chun Ryu, and Youn-Jung Kim declare that they have no conflicts of interest.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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The authors confirm that the data supporting findings of the present study are available within the article and its supplementary materials. Raw data supporting the results are available from the CONTACT corresponding author [duckyj@inu.ac.kr] on request.

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Choi, YE., Kim, MS., Ha, Y. et al. Association of expression of GADD family genes and apoptosis in human kidney proximal tubular (HK-2) cells exposed to nephrotoxic drugs. Mol. Cell. Toxicol. 18, 569–580 (2022). https://doi.org/10.1007/s13273-022-00231-3

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