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Renal Ischaemia Reperfusion Injury: A Mouse Model of Injury and Regeneration
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Vitamin D receptor attenuate ischemia-reperfusion kidney injury via inhibiting ATF4

Shiqi Tang1,2, Xueqin Wu1,2, Qing Dai1,2

  • 1Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China.

Cell Death Discovery
|May 12, 2023
PubMed

Insights

Vitamin D receptor (VDR) activation protects against acute kidney injury (AKI) by reducing endoplasmic reticulum stress (ERS) and suppressing Activating Transcription Factor 4 (ATF4) in mice.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Endocrinology

Background:

  • Endoplasmic reticulum stress (ERS) and Activating Transcription Factor 4 (ATF4) are implicated in acute kidney injury (AKI) progression.
  • Vitamin D receptor (VDR) activation has shown renoprotective effects in AKI models.
  • The precise role of VDR in modulating ERS and ATF4 during ischemia-reperfusion (I/R) induced AKI remains unclear.

Purpose of the Study:

  • To investigate the role of VDR in regulating ERS and ATF4 in the context of I/R-induced AKI.
  • To elucidate the molecular mechanisms underlying VDR's renoprotective effects.

Main Methods:

  • Utilized rodent models of I/R-induced AKI and tunicamycin (TM)-induced kidney injury.
  • Administered VDR agonist paricalcitol and employed VDR overexpression/deletion strategies.
  • Assessed renal injury, apoptosis, ATF4 levels, and ERS markers.
  • Performed bioinformatics analysis, ChIP-qPCR, and dual-luciferase reporter gene assays to confirm VDR-ATF4 interactions.

Main Results:

  • VDR activation (paricalcitol, overexpression) attenuated I/R- and TM-induced renal injury, apoptosis, ATF4, and ERS.
  • VDR deletion exacerbated renal injury, ATF4, and ERS in both models.
  • Overexpression of ATF4 partially reversed paricalcitol's protective effects, while ATF4 inhibition enhanced them.
  • VDR was found to bind to the ATF4 promoter region, indicating transcriptional regulation.

Conclusions:

  • VDR activation mitigates I/R-induced AKI by suppressing ERS.
  • This protective effect is partly mediated through the transcriptional regulation of ATF4 by VDR.
  • VDR represents a potential therapeutic target for managing AKI associated with ERS.

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