DNA damage response in renal ischemia-reperfusion and ATP-depletion injury of renal tubular cells

Zhengwei Ma, Qingqing Wei, Guie Dong, Yuqing Huo, Zheng Dong

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Renal ischemia-reperfusion leads to acute kidney injury (AKI) that is characterized pathologically by tubular damage and cell death, followed by tubular repair, atrophy and interstitial fibrosis. Recent work suggested the possible presence of DNA damage response (DDR) in AKI. However, the evidence is sketchy and the role and regulation of DDR in ischemic AKI remain elusive. In this study, we demonstrated the induction of phosphorylation of ATM, H2AX, Chk2 and p53 during renal ischemia-reperfusion in mice, suggesting DDR in kidney tissues. DDR was also induced in vitro during the recovery or "reperfusion" of renal proximal tubular cells (RPTCs) after ATP depletion. DDR in RPTCs was abrogated by supplying glucose to maintain ATP via glycolysis, indicating that the DDR depends on ATP depletion. The DDR was also suppressed by the general caspase inhibitor z-VAD and the overexpression of Bcl-2, supporting a role of apoptosis-associated DNA damage in the DDR. N-acetylcysteine (NAC), an antioxidant, suppressed the phosphorylation of ATM and p53 and, to a less extent, Chk2, but NAC increased the phosphorylation and nuclear foci formation of H2AX. Interestingly, NAC increased apoptosis, which may account for the observed H2AX activation. Ku55933, an ATM inhibitor, blocked ATM phosphorylation and ameliorated the phosphorylation of Chk2 and p53, but it increased H2AX phosphorylation and nuclear foci formation. Ku55933 also increased apoptosis in RPTCs following ATP depletion. The results suggest that DDR occurs during renal ischemia-reperfusion in vivo and ATP-depletion injury in vitro. The DDR is partially induced by apoptosis and oxidative stress-related DNA damage. ATM, as a sensor in the DDR, may play a cytoprotective role against tubular cell injury and death.

Original languageEnglish (US)
Pages (from-to)1088-1096
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1842
Issue number7
DOIs
StatePublished - Jul 2014

Keywords

  • ATP depletion
  • Acute kidney injury
  • Apoptosis
  • DNA damage response
  • Renal ischemia-reperfusion

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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