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

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...

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Published in:Molecular & cellular toxicology 2022, 18(4), , pp.569-580
Main Authors: Choi, Young-Eun, Kim, Mi-Soon, Ha, Yuna, Cho, Yoon, Kim, Jang Kyun, Rhee, Jae-Sung, Ryu, Jae-Chun, Kim, Youn-Jung
Format: Article
Language:English
Subjects:
Amphotericin B
Apoptosis
Biomedical and Life Sciences
Cell Biology
CHOP protein
Cisplatin
DNA damage
DNA microarrays
Drug development
Drug screening
Drugs
GADD34 protein
Gadd45A protein
Gene expression
Geneticin
Kidneys
Life Sciences
MAP kinase
Oligonucleotides
Original Article
Pharmacology/Toxicology
Phosphorylation
생물학
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Summary: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.
ISSN:1738-642X
2092-8467
DOI:10.1007/s13273-022-00231-3