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Abstract: PO0170

DNA Repair Factor KAT5 Acts Against Ischemia-Reperfusion Injury Through Promoted DNA Repair and KCC3-Dependent TGF Regulation in Proximal Tubular Cells

Session Information

  • AKI Mechanisms - 1
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • Hishikawa, Akihito, Keio University School of Medicine, Tokyo, Japan
  • Hayashi, Kaori, Keio University School of Medicine, Tokyo, Japan
  • Monkawa, Toshiaki, Keio University School of Medicine, Tokyo, Japan
  • Itoh, Hiroshi, Keio University School of Medicine, Tokyo, Japan

It is known that an episode of ischemia-reperfusion (IR) results in tolerance to subsequent IR, which is so-called “pre-conditioning (PC) effect”. However, the molecular mechanisms of the pre-conditioning effect have not been adequately elucidated. We have recently discovered that DNA double strand break (DSB) repair factor KAT5 is essential for maintenance of podocyte integrity (Cell Rep. 2019). Here we investigated the role of KAT5 in PC effect.


Wild-type (WT) mice and proximal tubular epithelial cell (PTEC)-specific KAT5 knockout (KO) mice underwent IR injury by clamping bilateral renal arteries for 30 minutes followed by reperfusion. Ischemic pre-conditioning was performed 1 week prior to IR injury. In vitro studies using cultured human PTECs (HK2 cells) were conducted with ATP depletion by Antymicin A (AMA), an in vitro model of acute tubular cell damage.


Serum UN, Cr, urine NGAL, DNA DSB marker γH2AX and KAT5 expression of the PTECs were increased and chloride transoporter KCC3 expression was decreased at 24 hours after IR. IR with PC showed an attenuated increase in serum UN, Cr, urine NGAL and DNA DSBs with accelerated KAT5 and KCC3 expression. Mass spectrometry imaging of the kidney cortex following the first IR demonstrated elevated glomerular adenosine, which is used as a marker of accelerated tubule-glomerular feedback (TGF), whereas it was decreased after the second IR with PC in WT mice, suggesting attenuated TGF in the second IR. Therefore, increased chloride uptake through KCC3 in PTECs may contribute to the suppression of TGF, which maintained GFR. In KAT5 KO mice, PC effect was attenuated with increased DNA damage and decreased KCC3 expression. In vitro ATP depletion studies showed elevated KAT5 and KCC3 expression following second treatment with AMA. Chromatin accessibility assay showed promoted chromatin accessibility of the KCC3 promoter region after the second treatment with AMA. ChIP analysis revealed that KAT5-binding KCC3 promoter region was significantly increased after the second injury compared with the first injury, indicating that elevated KCC3 expression was caused by increased binding of KAT5 to the KCC3 promoter region.


PTEC KAT5 may act against IR injury through promoted DNA repair and regulation of TGF via KCC3 expression.