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Modeling Hypoxia/Reoxygenation Injury in Proximal Tubular Epithelial Cells
Published on: November 21, 2025
Transcription factor Nrf2 hyperactivation in early-phase renal ischemia-reperfusion injury prevents tubular damage
Masahiro Nezu1, Tomokazu Souma2, Lei Yu3
1Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; Division of Oxygen Biology, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University Graduate School of Medicine, Sendai, Japan.
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.
Insights
Activating Nrf2 in kidney tubules protects against oxidative stress and damage during acute kidney injury. This targeted approach may prevent the transition from acute kidney injury to chronic kidney disease.
Area of Science:
- Nephrology
- Molecular Biology
- Oxidative Stress Research
Background:
- Acute kidney injury (AKI) is a severe condition with high morbidity, often leading to chronic kidney disease (CKD).
- Ischemia-reperfusion injury (IRI) is a key mechanism in AKI, causing oxidative stress and organ damage.
- Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial transcription factor regulating cellular antioxidant responses.
Purpose of the Study:
- To investigate the role of Nrf2 in IRI-induced kidney damage using genetic and pharmacological methods.
- To determine if activating Nrf2 in specific kidney cell types can mitigate IRI-induced damage.
- To explore Nrf2's potential as a therapeutic target for preventing AKI progression to CKD.
Main Methods:
- Utilized global and tubular-specific Nrf2 activation in mouse models of IRI.
- Administered the Nrf2 inducer CDDO during the acute phase of injury.
- Assessed gene expression of antioxidant and NADPH synthesis enzymes (e.g., glucose-6-phosphate dehydrogenase).
- Evaluated tubular damage in the outer medulla and cortex.
- Tested CDDO efficacy on human proximal tubular cells (HK-2) and the impact of glucose-6-phosphate dehydrogenase knockdown.
Main Results:
- Global and tubular Nrf2 activation enhanced antioxidant and NADPH synthesis, reducing outer medulla injury and cortical tubular damage.
- Myeloid-specific Nrf2 activation showed no protective effect.
- Short-term CDDO administration during initial injury ameliorated later tubular damage.
- CDDO protected HK-2 cells from oxidative stress; G6PD knockdown increased reactive oxygen species.
Conclusions:
- Tubular Nrf2 hyperactivation in early IRI phases prevents reactive oxygen species-mediated damage by boosting antioxidant enzymes and NADPH synthesis.
- Nrf2 activation in kidney tubules is a promising strategy to prevent AKI progression to CKD.
- Targeting tubular Nrf2 may offer a novel therapeutic avenue for AKI patients.
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