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Inhibition of PLK3 Attenuates Tubular Epithelial Cell Apoptosis after Renal Ischemia-Reperfusion Injury by Blocking

Weiming Deng1,2, Xiangling Wei1, Zhenwei Xie1

  • 1Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China.

Oxidative Medicine and Cellular Longevity
|July 5, 2022
PubMed
Abstract

Insights

Polo-like kinase 3 (PLK3) exacerbates renal ischemia-reperfusion (I/R) injury by promoting oxidative stress and tubular epithelial cell (TEC) apoptosis. Inhibiting PLK3 protects kidneys from I/R injury by blocking the DNA damage response (DDR).

Area of Science:

  • Nephrology
  • Molecular Biology
  • Cellular Biology

Background:

  • Renal ischemia-reperfusion (I/R) injury is a primary cause of acute kidney injury (AKI) in kidney transplants.
  • The molecular mechanisms underlying renal I/R injury, particularly the role of oxidative stress and apoptosis, require further elucidation.

Purpose of the Study:

  • To investigate the role of polo-like kinase 3 (PLK3) in renal I/R injury.
  • To explore the relationship between PLK3, oxidative stress, DNA damage, and renal tubular epithelial cell (TEC) apoptosis in the context of I/R injury.

Main Methods:

  • Analysis of transcriptomic data (GSE52004, GSE121191) to assess PLK3 expression.
  • In vitro studies using hypoxia/reoxygenation (H/R) models with PLK3 overexpression or silencing (siRNA).
  • In vivo studies using C57BL/6J mice subjected to I/R injury, treated with rAAV-9-PLK3-KD, and administered the ATM inhibitor KU-60019.
  • Assessment of cell viability, apoptosis (flow cytometry, TUNEL), reactive oxygen species (ROS) production, oxidative stress markers (MDA, SOD), and kidney injury markers (KIM-1, Scr, BUN).

Main Results:

  • PLK3 expression was significantly upregulated in both H/R and I/R injury models.
  • PLK3 overexpression increased TEC apoptosis, while PLK3 silencing reduced apoptosis by decreasing P53 phosphorylation and the Bax/Bcl-2 ratio.
  • Inhibition of the DNA damage response (DDR) pathway via KU-60019 reduced PLK3 activation and apoptosis; PLK3 overexpression counteracted this protective effect.
  • Mice treated with rAAV-9-PLK3-KD showed reduced TEC apoptosis and attenuated renal damage following I/R injury.

Conclusions:

  • PLK3 plays a critical role in mediating oxidative stress-induced DNA damage and TEC apoptosis during renal I/R injury.
  • Inhibition of PLK3 ameliorates renal I/R injury by suppressing the ATM/P53-mediated DDR pathway.
  • PLK3 represents a potential therapeutic target for managing ischemic AKI.

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