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Cited by 21Chemotherapy-induced organ toxicity mitigationTelomeres, Telomerase, and SenescenceAcute Kidney Injury Research

In vitro study on effect of bardoxolone methyl on cisplatin-induced cellular senescence in human proximal tubular cells

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Kurosaki, Yoshifumi, Imoto, Akemi, Kawakami, Fumitaka, Ouchi, Motoshi, Morita, Asuka, Yokoba, Masanori, Takenaka, Tsuneo, Ichikawa, Takafumi +3 more·2022·Molecular and Cellular Biochemistry
DOI 10.1007/s11010-021-04295-yPMC PMC8857011
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Abstract

Bardoxolone methyl [methyl-2-cyano-3, 12-dioxooleana-1, 9(11)dien-28-oate (CDDO-Me)], an activator of the nuclear factor erythroid-derived 2-related factor2 pathway, is a potential therapeutic candidate for the treatment of kidney diseases. However, its effect against cellular senescence remains unclear. This study aimed to investigate whether CDDO-Me protects cells against cisplatin-induced cellular senescence using an in vitro model. The human renal proximal tubular epithelial cell line HK-2 was treated with cisplatin for 6 h, followed by treatment with or without CDDO-Me (0.1 or 0.2 μmol/L). Senescence markers were analyzed using western blotting and real-time PCR. Apoptosis was evaluated through TUNEL staining. Cisplatin induced changes in the levels of markers specific for proliferation, cell cycle, and senescence in a time- and dose-dependent manner. Furthermore, IL-6 and IL-8 levels in the culture medium increased markedly. These data suggested that cellular senescence-like alterations occurred in HK-2 cells exposed to cisplatin. CDDO-Me treatment reversed the cisplatin-mediated alterations in the levels of cellular senescence markers. The antioxidant enzymes, HO1 , NQO1 , GPX1 , and CAT were upregulated by CDDO-Me treatment. Furthermore, CDDO-Me treatment induced apoptosis in cisplatin-exposed HK-2 cells. Pretreatment with Ac-DEVD-CHO, the caspase inhibitor, suppressed the reversal effect of CDDO-Me against cisplatin-induced cellular senescence-like alterations. This study showed that CDDO-Me attenuated cisplatin-induced premature senescence of HK-2 cells. This beneficial effect may be related to Nrf2 activation. Our findings also showed that CDDO-Me induced apoptosis in cisplatin-treated HK-2 cells, potentially protecting the kidneys from cellular senescence. CDDO-Me appears to be a candidate treatment for acute kidney injury.

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  • CDDO is a synthesized triterpenoid that potently activates Nrf2, promotes its nuclear translocation, and induces expression of downstream antioxidant proteins such as NQO1 and HO-1.

    “CDDO is a synthesized triterpenoid that potently activates Nuclear factor erythroid 2–related factor 2 (Nrf2), promotes its nuclear translocation (Kurosaki et al., 2022), and induces the expression of downstream antioxidant proteins such as NAD(P)H quinone dehydrogenase 1 (NQO1) and heme oxygenase 1 (HO-1) (Liby et al., 2005).”

    From Material-dependent oxygen transport governs ischemia-reperfusion injury and drug response in a kidney microphysiological system (2026) · cites this paper as Kurosaki et al., 2022

    The Introduction calls CDDO-Me (bardoxolone methyl) a semi-synthetic triterpenoid and potent Nrf2-pathway activator; the Discussion says Nrf2 translocates to the nucleus upon activation by CDDO-Me. The citing sentence instead says CDDO, which the paper does not equate with CDDO-Me. The NQO1 and HO-1 clause is attached to a different citation, so it is not judged against Kurosaki et al. No page numbers are available in our copy. (LLM, conf=0.88)

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Cited by

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Authors
Kurosaki, Y., Imoto, A., Kawakami, F., Ouchi, M., Morita, A., Yokoba, M., Takenaka, T., Ichikawa, T., Katagiri, M., Nielsen, R., & Ishii, N.
Affiliations
  • Kitasato University (JP)
  • Dokkyo Medical University (JP)
  • International University of Health and Welfare (JP)
  • Aarhus University (DK)
Corresponding author
Kurosaki, Yoshifumi
ORCID
Venue
Molecular and Cellular Biochemistry
Publisher
Springer Science and Business Media LLC
Published
2022-01-01
Volume
477
Issue
3
Pages
689-699
ISSN
  • 0300-8177 (ISSN-L)
  • 1573-4919
DOI
10.1007/s11010-021-04295-y
PMC
PMC8857011
OpenAlex
W4205097611
Cited by
21
References
5
Citations by year
2026: 5 · 2025: 6 · 2024: 7 · 2023: 1 · 2022: 2
FWCI
2.66
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular and Cellular Biochemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Kitasato University School of Allied Health Sciences (Grant-in-Aid for Research Project, 2021-1022, 2019-1053, 2020-1047)
  • JSPS KAKENHI (Grant-in-Aid for Scientific Research (C) No. JP19K07944)
  • Kitasato University (Research Grant for Young Researchers 2019-19)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Chemotherapy-induced organ toxicity mitigation
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
Keywords
bardoxolone methyl, cisplatin, cellular senescence, Nrf2, HK-2 cells, renal proximal tubular epithelial cells, apoptosis, acute kidney injury, oxidative stress, antioxidant enzymes, caspases, interleukin-6, interleukin-8
MeSH terms
Cell Line, Cisplatin, Humans, Kidney Tubules, Proximal, Oleanolic Acid, Cellular Senescence

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