Open Access

Gene networking in colistin-induced nephrotoxicity reveals an adverse outcome pathway triggered by proteotoxic stress

  • Authors:
    • Eun Hee Lee
    • Soojin Kim
    • Mi-Sun Choi
    • Heeyoung Yang
    • Se-Myo Park
    • Hyun-A Oh
    • Kyoung-Sik Moon
    • Ji-Seok Han
    • Yong-Bum Kim
    • Seokjoo Yoon
    • Jung-Hwa Oh
  • View Affiliations

  • Published online on: January 8, 2019     https://doi.org/10.3892/ijmm.2019.4052
  • Pages: 1343-1355
  • Copyright: © Lee et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Colistin has been widely used for the treatment of infections of multidrug‑resistant Gram‑negative bacteria, despite the fact that it induces serious kidney injury as a side effect. To investigate the mechanism underlying its nephrotoxicity, colistin methanesulfonate sodium (CMS; 25 or 50 mg/kg) was administered via intraperitoneal injection to Sprague‑Dawley rats daily over 7 days. Serum biochemistry and histopathology indicated that nephrotoxicity occurred in the rats administered with CMS. Whole‑genome microarrays indicated 894 differentially expressed genes in the group treated with CMS (analysis of variance, false discovery rate <0.05, fold‑change ≥1.3). Gene pathway and networking analyses revealed that genes associated with proteotoxic stress, including ribosome synthesis, protein translation, and protein folding, were significantly associated with the nephrotoxicity induced by CMS. It was found that colistin inhibited the expression of the target genes heat shock factor 1 and nuclear factor erythroid‑2‑related factor‑2, which are associated with proteostasis, and that nephrotoxicity of CMS may be initiated by proteotoxic stress due to heat shock response inhibition, leading to oxidative stress, endoplasmic reticulum stress, cell cycle arrest and apoptosis, eventually leading to cell death. A putative adverse outcome pathway was constructed based on the integrated gene networking data, which may clarify the mode of action of colistin‑induced nephrotoxicity.
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March-2019
Volume 43 Issue 3

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Lee EH, Kim S, Choi M, Yang H, Park S, Oh H, Moon K, Han J, Kim Y, Yoon S, Yoon S, et al: Gene networking in colistin-induced nephrotoxicity reveals an adverse outcome pathway triggered by proteotoxic stress. Int J Mol Med 43: 1343-1355, 2019
APA
Lee, E.H., Kim, S., Choi, M., Yang, H., Park, S., Oh, H. ... Oh, J. (2019). Gene networking in colistin-induced nephrotoxicity reveals an adverse outcome pathway triggered by proteotoxic stress. International Journal of Molecular Medicine, 43, 1343-1355. https://doi.org/10.3892/ijmm.2019.4052
MLA
Lee, E. H., Kim, S., Choi, M., Yang, H., Park, S., Oh, H., Moon, K., Han, J., Kim, Y., Yoon, S., Oh, J."Gene networking in colistin-induced nephrotoxicity reveals an adverse outcome pathway triggered by proteotoxic stress". International Journal of Molecular Medicine 43.3 (2019): 1343-1355.
Chicago
Lee, E. H., Kim, S., Choi, M., Yang, H., Park, S., Oh, H., Moon, K., Han, J., Kim, Y., Yoon, S., Oh, J."Gene networking in colistin-induced nephrotoxicity reveals an adverse outcome pathway triggered by proteotoxic stress". International Journal of Molecular Medicine 43, no. 3 (2019): 1343-1355. https://doi.org/10.3892/ijmm.2019.4052