Hypoxia-Inducible Factor 1α Drives Cellular Senescence by Autophagy to Promote AKI-to-CKD Transition

Background: Hypoxia, cellular senescence, and autophagy are interconnected processes that play significant roles in the development and progression of acute kidney injury (AKI) and chronic kidney disease (CKD). However, the crosstalk effect of hypoxia, cellular senescence, and autophagy on AKI transition to CKD was unclear. Methods: We perform western blot, qRT-PCR, and histological, IF and IHC staining to determine the dynamics of Hypoxia-Inducible Factor 1 alpha (HIF-1α) and its relationship with autophagy and senescence in hypoxia-reoxygenation human renal proximal tubule cells (HK-2), adaptive repair (AR) or maladaptive repair (MAR) of ischemia reperfusion injury mouse model, as well as the CKD patients. Results: We found that the expression of HIF-1α, senescence (p16 and p21), and autophagy (Beclin-1 and LC3B) was transiently increased, all of them recovered to the baseline in the AR group. However, the expression of HIF-1α, senescence and autophagy were progressively increased in the MAR group. The dynamics of HIF-1α, autophagy, and senescence exhibited a positive correlation, suggesting HIF-1α may influence senescence and autophagic activity in the hypoxic condition to promote the progression of AKI to CKD. In vitro, we found that knockdown of HIF-1α decreased senescence (p16 and p21), autophagy (Beclin-1 and LC3B) and decreased the epithelial-mesenchymal transition (EMT) in the hypoxia-reoxygenation HK-2 cells. However, treatment with the autophagy activator Rapamycin increased the senescence and EMT. In contrast, the overexpression of HIF-1α increased senescence (p16 and p21), autophagy (Beclin-1 and LC3B) and EMT in hypoxia-reoxygenation HK-2 cells. Treatment with the autophagy inhibitor Bafilomycin A1 decreased senescence and EMT. We also found that the expression of HIF-1α was increased in the kidneys from CKD patients, and its expression was significantly correlated with the levels of estimated glomerular filtration rate (eGFR), senescence and renal fibrosis. Conclusion: The rapid and adequate expression of HIF-1α during the initial phase of AKI induces acute cellular senescence and facilitates kidney repair. While the persistent expression of HIF-1α drives chronic cellular senescence by constantly activating autophagy and may facilitate the transition from AKI to CKD.