Suppression of NRF2 Activity by HIF-1α Promotes Fibrosis after Ischemic Acute Kidney Injury

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-1 alpha (HIF-1 alpha) mediates NRF2 activity. To mimic mild and severe ischemia, we activated HIF-1 alpha in HK-2 cells in nutrient-replete or nutrient-deficient conditions. HIF-1 alpha activation in nutrient-replete conditions enhanced NRF2 nuclear localization and activity. However, in nutrient-deficient conditions, HIF-1 alpha activation suppressed NRF2 nuclear localization and activity. Nuclear localization was rescued with HIF-1 alpha siRNA knockdown. Our results suggest that severe ischemic AKI leads to HIF-1 alpha-mediated suppression of NRF2, leading to AKI-to-CKD progression.