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Aristolochic acid-induced apoptosis and G2 cell cycle arrest depends on ROS generation and MAP kinases activation

  • Molecular Toxicology
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Abstract

Ingestion of aristolochic acids (AAs) contained in herbal remedies results in a renal disease and, frequently, urothelial malignancy. The genotoxicity of AA in renal cells, including mutagenic DNA adducts formation, is well documented. However, the mechanisms of AA-induced tubular atrophy and renal fibrosis are largely unknown. To better elucidate some aspects of this process, we studied cell cycle distribution and cell survival of renal epithelial cells treated with AAI at low and high doses. A low dose of AA induces cell cycle arrest in G2/M phase via activation of DNA damage checkpoint pathway ATM–Chk2–p53–p21. DNA damage signaling pathway is activated more likely via increased production of reactive oxygen species (ROS) caused by AA treatment then via DNA damage induced directly by AA. Higher AA concentration induced cell death partly via apoptosis. Since mitogen-activated protein kinases play an important role in cell survival, death and cell cycle progression, we assayed their function in AA-treated renal tubular epithelial cells. ERK1/2 and p38 but not JNK were activated in cells treated with AA. In addition, pharmacological inhibition of ERK1/2 and p38 as well as suppression of ROS generation with N-acetyl-l-cysteine resulted in the partial relief of cells from G2/M checkpoint and a decline of apoptosis level. Cell cycle arrest may be a mechanism for DNA repair, cell survival and reprogramming of epithelial cells to the fibroblast type. An apoptosis of renal epithelial cells at higher AA dose might be necessary to provide space for newly reprogrammed fibrotic cells.

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Acknowledgments

This work was financially supported by the National Institutes of Health Grant P01ES004068 to Arthur P. Grollman.

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Authors and Affiliations

  1. Department of Urology, SUNY at Stony Brook HSC, T09, Rm. 050, Stony Brook, NY, 11794, USA

    Victor Romanov, Terry C. Whyard & Wayne C. Waltzer

  2. Department of Pharmacological Sciences, SUNY at Stony Brook, Stony Brook, NY, 11794, USA

    Arthur P. Grollman & Thomas Rosenquist

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  1. Victor Romanov
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  2. Terry C. Whyard
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  4. Arthur P. Grollman
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Correspondence to Victor Romanov.

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Romanov, V., Whyard, T.C., Waltzer, W.C. et al. Aristolochic acid-induced apoptosis and G2 cell cycle arrest depends on ROS generation and MAP kinases activation. Arch Toxicol 89, 47–56 (2015). https://doi.org/10.1007/s00204-014-1249-z

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  • DOI: https://doi.org/10.1007/s00204-014-1249-z

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