HIF-1α mediated ferroptosis is a critical target for renal prognosis in septic shock rats receiving VA-ECMO support

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a potential life-support treatment for septic shock patients with severe myocardial depression, but its effects on renal function in this context remain unclear. This study aimed to investigate the impact of VA-ECMO on kidney of septic shock in animal experiments and explore the underlying molecular mechanism targets.

The stable VA-ECMO model was established in septic shock rats. The ultrasonography, histopathological evaluation, RNA sequencing, metabolomic profiling, and protein expression analysis were conducted to comprehensively assess renal status and investigated the underlying molecular mechanisms.

VA-ECMO treatment effectively reinstated circulation, ensures adequate tissue oxygenation, increased blood supply to the kidney, attenuated renal tissue injury in the early resuscitative phase of a rat model of septic shock. Furthermore, we noticed that the VA-ECMO inhibited ferroptosis, shown as the prevention of the higher total iron, Fe 2+ , MDA, and ROS levels in septic shock rat model. According to RNA and metabolome sequencing analysis, the inhibition of renal ferroptosis during VA-ECMO was associated with hypoxia-inducible factor-1α (HIF-1α) signaling inhibition. In addition, we discovered transferrin receptor 1 (TFR1) and divalent metal transporter 1 (DMT1), which were the key factors of ferroptosis and down-stream proteins of HIF-1α, were significantly downregulated. Additional animal experiments confirmed that the regulation HIF-1α expression during VA-ECMO treatment in septic shock rats affects renal iron deposition, ferroptosis, and injury level and the regulation of oxygenation at the membrane oxygenator is a critical upstream mediator.

This study reveals that timely VA-ECMO support in septic shock rats protects the kidneys by synergistically restoring macro-circulatory perfusion and optimizing oxygen delivery. The regulation of the HIF-1α-ferroptosis axis is established as a critical mechanistic component of this protection, with its activity being dependent on the oxygen content delivered by the VA-ECMO circuit.