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ORIGINAL RESEARCH article

Front. Cell Dev. Biol.
Sec. Cell Death and Survival
Volume 12 - 2024 | doi: 10.3389/fcell.2024.1457369

DNA damage-induced AIM2 pyroptosis in high glucose-induced proximal tubular epithelial cell

Provisionally accepted
Lu'an Li Lu'an Li 1,2*Li Zhang Li Zhang 2*Yating Cai Yating Cai 2*Jiaying Li Jiaying Li 2*Siqi Zheng Siqi Zheng 2*Weiteng Wang Weiteng Wang 1,2*Yinwen Chen Yinwen Chen 1,2*Jieyi Luo Jieyi Luo 2*Ruizhao Li Ruizhao Li 2,3,4*Xinling Liang Xinling Liang 1,2*
  • 1 School of Medicine, South China University of Technology, Guangzhou, Guangdong Province, China
  • 2 Guangdong Academy of Medical Sciences, Southern Medical University, Department of Nephrology, Guangdong Provincial People’s Hospital, Guangzhou, China
  • 3 Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital,Guangdong Academy of Medical Sciences, Guangzhou, China
  • 4 Ganzhou Hospital of Guangdong Provincial People's Hospital, Ganzhou Municipal Hospital, Guangzhou, China

The final, formatted version of the article will be published soon.

    Pyroptosis is one of the ways to cause proximal tubular epithelial cell death in diabetic nephropathy (DN), but the exact mechanism remains unclear. Absent in melanoma 2 (AIM2), a sensor for double-stranded DNA, creates an inflammasome that triggers the cleavage of gasdermin D (GSDMD), leading to a type of inflammatory cell death called pyroptosis. This study investigated the role of AIM2 in pyroptosis within proximal tubular epithelial cells in DN.We observed significantly elevated AIM2 expression in renal tubules from DN patients and db/db mice, as well as in high glucose (HG)-induced Human Kidney-2 (HK2) cells. Besides, increased AIM2 expression was accompanied by activation of the pyroptosis pathway (cleaved-caspase-1, GSDMD-FL, GSDMD-NT) in the renal cortex of db/db mice and HG-induced HK2 cells in vitro.Knocking down GSDMD can reduce HG-induced HK2 cell death, indicating that HG triggers pyroptosis in HK2 cells. Furthermore, HG-induced pyroptosis was mitigated in HK2 cells with AIM2 knockdown using siRNA. Additionally, reducing ROS levels using NAC was able to attenuate HG-induced HK2 cells DNA damage, AIM2 activation, and pyroptosis. Notably, AIM2 upregulation was observed in renal biopsies from DN patients, with expression levels positively correlating with serum creatinine and inversely with estimated glomerular filtration rate (eGFR).Collectively, DNA damage caused by HG could result in the activation of the AIM2 inflammasome, leading to the pyroptosis of proximal tubular epithelial cells, indicating that targeting AIM2 could be a potential novel approach for treating DN.

    Keywords: AIM2, pyroptosis, diabetic nephropathy, DNA Damage, high glucose

    Received: 30 Jun 2024; Accepted: 13 Nov 2024.

    Copyright: © 2024 Li, Zhang, Cai, Li, Zheng, Wang, Chen, Luo, Li and Liang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Lu'an Li, School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong Province, China
    Li Zhang, Guangdong Academy of Medical Sciences, Southern Medical University, Department of Nephrology, Guangdong Provincial People’s Hospital, Guangzhou, China
    Yating Cai, Guangdong Academy of Medical Sciences, Southern Medical University, Department of Nephrology, Guangdong Provincial People’s Hospital, Guangzhou, China
    Jiaying Li, Guangdong Academy of Medical Sciences, Southern Medical University, Department of Nephrology, Guangdong Provincial People’s Hospital, Guangzhou, China
    Siqi Zheng, Guangdong Academy of Medical Sciences, Southern Medical University, Department of Nephrology, Guangdong Provincial People’s Hospital, Guangzhou, China
    Weiteng Wang, Guangdong Academy of Medical Sciences, Southern Medical University, Department of Nephrology, Guangdong Provincial People’s Hospital, Guangzhou, China
    Yinwen Chen, School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong Province, China
    Jieyi Luo, Guangdong Academy of Medical Sciences, Southern Medical University, Department of Nephrology, Guangdong Provincial People’s Hospital, Guangzhou, China
    Ruizhao Li, Guangdong Academy of Medical Sciences, Southern Medical University, Department of Nephrology, Guangdong Provincial People’s Hospital, Guangzhou, China
    Xinling Liang, School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong Province, China

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