Hypoxia-Inducible Factor-1α Drives Cellular Senescence via Autophagy Activation to Promote Acute Kidney Injury-to-CKD...

Ischemia and hypoxia are central drivers of acute kidney injury (AKI), and hypoxia-inducible factor (HIF) is a key regulator of cellular oxygen homeostasis. Our previous study showed that HIF-1α is protective during the early stage of AKI; however, its role in the transition from AKI to chronic kidney disease (CKD) remains unclear. Cellular senescence has been implicated in CKD progression and can be accelerated by hypoxia. Nevertheless, whether HIF-1α signaling mediates cellular senescence and promotes the AKI-to-CKD transition is poorly understood.

Ischemia-reperfusion injury models of AKI with adaptive repair (AR) or maladaptive repair (MAR) were used to examine the dynamics of HIF-1α, cellular senescence, and autophagy. In human renal proximal tubular epithelial cells (HK-2), a hypoxia/reoxygenation (H/R) injury model was used to evaluate the relationships among HIF-1α, autophagy, and senescence. Finally, the association between HIF-1α levels and cellular senescence was assessed in renal biopsies from CKD patients.

The AR group exhibited rapid and sufficient HIF-1α expression, accompanied by acute senescence, with HIF-1α levels returning to baseline upon the completion of repair. In contrast, the MAR group showed delayed and sustained HIF-1α activation, driving chronic senescence and progressive fibrosis. The activation of autophagy was closely associated with the expression of HIF-1α in the AR and MAR groups. In vitro, silencing HIF-1α expression attenuated autophagy activity, senescence, and fibrosis in HK-2 cells under H/R. However, HIF-1α overexpression had the opposite effect. The autophagy activator rapamycin reversed the inhibitory effects of HIF-1α knockdown, whereas the autophagy inhibitor bafilomycin A1 diminished the pro-senescent and pro-fibrotic effects of HIF-1α overexpression. Analysis of CKD patient biopsies confirmed elevated HIF-1α expression, which correlated with reduced eGFR, increased fibrosis, and enhanced cellular senescence.

Adequate HIF-1α activation during early AKI is associated with acute senescence and renal repair, whereas sustained HIF-1α drives chronic senescence via persistent autophagy activation and may contribute to the AKI-to-CKD transition.