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Updated: Aug 28, 2025
Ischemia-reperfusion Model of Acute Kidney Injury and Post Injury Fibrosis in Mice
Published on: August 9, 2013
Suppression of NRF2 Activity by HIF-1α Promotes Fibrosis after Ischemic Acute Kidney Injury
Corry D Bondi1, Brittney M Rush1, Hannah L Hartman1
1Department of Medicine, University of Pittsburgh, Pittsburgh, PA 152671, USA.
Abstract:
Acute kidney injury (AKI) is a rapid decline in renal function and can occur after ischemia/reperfusion injury (IRI) to the tubular epithelia. The nuclear factor erythroid-2-related factor 2 (NRF2) pathway protects against AKI and AKI-to-chronic kidney disease (CKD) progression, but we previously demonstrated that severe IRI maladaptively reduced NRF2 activity in mice. To understand the mechanism of this response, we subjected C57BL/6J mice to unilateral kidney IRI with ischemia times that were titrated to induce mild to severe injury. Mild IRI increased NRF2 activity and was associated with renal recovery, whereas severe IRI decreased NRF2 activity and led to progressive CKD. Due to these effects of ischemia, we tested the hypothesis that hypoxia-inducible factor-1α (HIF-1α) mediates NRF2 activity. To mimic mild and severe ischemia, we activated HIF-1α in HK-2 cells in nutrient-replete or nutrient-deficient conditions. HIF-1α activation in nutrient-replete conditions enhanced NRF2 nuclear localization and activity. However, in nutrient-deficient conditions, HIF-1α activation suppressed NRF2 nuclear localization and activity. Nuclear localization was rescued with HIF-1α siRNA knockdown. Our results suggest that severe ischemic AKI leads to HIF-1α-mediated suppression of NRF2, leading to AKI-to-CKD progression.
Insights
Severe kidney injury impairs the protective NRF2 pathway via HIF-1α, promoting progression from acute kidney injury (AKI) to chronic kidney disease (CKD). Mild injury, however, enhances NRF2 and aids recovery.
Area of Science:
- Nephrology
- Molecular Biology
- Cellular Biology
Background:
- Acute kidney injury (AKI) involves rapid renal function decline, often after ischemia/reperfusion injury (IRI).
- The nuclear factor erythroid-2-related factor 2 (NRF2) pathway is crucial for protecting against AKI and progression to chronic kidney disease (CKD).
- Previous studies showed severe IRI maladaptively reduces NRF2 activity in mice.
Purpose of the Study:
- To investigate the mechanism by which severe ischemia reduces NRF2 activity following AKI.
- To determine if hypoxia-inducible factor-1α (HIF-1α) mediates the effect of ischemia on NRF2 activity.
- To understand how NRF2 regulation by HIF-1α influences AKI-to-CKD progression.
Main Methods:
- Mice underwent unilateral kidney IRI with titrated ischemia times to induce varying injury severity.
- NRF2 activity was assessed in relation to injury severity and renal recovery or CKD progression.
- Hypoxia-inducible factor-1α (HIF-1α) was activated in HK-2 cells under nutrient-replete and nutrient-deficient conditions to mimic ischemia.
- NRF2 nuclear localization and activity were measured, with HIF-1α siRNA used for knockdown experiments.
Main Results:
- Mild IRI increased NRF2 activity, correlating with renal recovery.
- Severe IRI decreased NRF2 activity, leading to progressive CKD.
- HIF-1α activation enhanced NRF2 in nutrient-replete cells but suppressed it in nutrient-deficient cells.
- HIF-1α-mediated suppression of NRF2 was reversible with siRNA knockdown.
Conclusions:
- Severe ischemic AKI results in HIF-1α-mediated suppression of the protective NRF2 pathway.
- This suppression contributes to the progression of AKI to CKD.
- Understanding this mechanism offers potential therapeutic targets for preventing CKD after AKI.
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