Transcription factor Nrf2 hyperactivation in early-phase renal ischemia-reperfusion injury prevents tubular damage progression

Masahiro Nezu, Tomokazu Souma, Lei Yu, Takafumi Suzuki, Daisuke Saigusa, Sadayoshi Ito, Norio Suzuki, Masayuki Yamamoto

Research output: Contribution to journalArticlepeer-review

60 Citations (Scopus)

Abstract

Acute kidney injury is a devastating disease with high morbidity in hospitalized patients and contributes to the pathogenesis of chronic kidney disease. An underlying mechanism of acute kidney injury involves ischemia-reperfusion injury which, in turn, induces oxidative stress and provokes organ damage. Nrf2 is a master transcription factor that regulates the cellular response to oxidative stress. Here, we examined the role of Nrf2 in the progression of ischemia-reperfusion injury-induced kidney damage in mice using genetic and pharmacological approaches. Both global and tubular-specific Nrf2 activation enhanced gene expression of antioxidant and NADPH synthesis enzymes, including glucose-6-phosphate dehydrogenase, and ameliorated both the initiation of injury in the outer medulla and the progression of tubular damage in the cortex. Myeloid-specific Nrf2 activation was ineffective. Short-term administration of the Nrf2 inducer CDDO during the initial phase of injury ameliorated the late phase of tubular damage. This inducer effectively protected the human proximal tubular cell line HK-2 from oxidative stress-mediated cell death while glucose-6-phosphate dehydrogenase knockdown increased intracellular reactive oxygen species. These findings demonstrate that tubular hyperactivation of Nrf2 in the initial phase of injury prevents the progression of reactive oxygen species-mediated tubular damage by inducing antioxidant enzymes and NADPH synthesis. Thus, Nrf2 may be a promising therapeutic target for preventing acute kidney injury to chronic kidney disease transition.

Original languageEnglish
Pages (from-to)387-401
Number of pages15
JournalKidney international
Volume91
Issue number2
DOIs
Publication statusPublished - 2017 Feb 1

Keywords

  • acute kidney injury
  • chronic kidney disease
  • ischemia reperfusion
  • oxidative stress
  • transcription regulation

ASJC Scopus subject areas

  • Nephrology

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