Activation of the NF-κB Signalling Pathway by Angiotensin II Aggravates Renal Inflammatory Injury During Non-Pulsatile Perfusion

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OBJECTIVES: Non-pulsatile perfusion is a widely used mode of blood flow in extracorporeal life support (ECLS). In contrast to physiological pulsatile perfusion, non-pulsatile perfusion has been linked to renal injury. This study aims to investigate the differential effects of pulsatile and non-pulsatile perfusion on renal injury. METHODS: We utilized a previously established ECLS model in Sprague-Dawley rats (n = 6 per group). Non-pulsatile and pulsatile perfusion were modelled using veno-arterial (VA) and veno-venous (VV) extracorporeal membrane oxygenation (ECMO) modes, respectively, to emulate the haemodynamic features of different flow patterns. Following 4 hours of perfusion, serum and renal tissue samples were collected for analysis. Renal injury biomarkers, including blood urea nitrogen (BUN), serum creatinine (Scr), kidney injury molecule 1 (KIM-1), and cystatin C (Cys-C), were quantified. Transcriptomic analysis, Western blotting, and quantitative real-time polymerase chain reaction (PCR) were employed to explore molecular mechanisms. In the non-pulsatile group, a treatment subgroup was administered captopril (50 mg/kg, intraperitoneally, 15 min before perfusion) to evaluate the role of Ang II in renal injury. RESULTS: Compared with the non-pulsatile group, the pulsatile perfusion group showed lower levels of biomarkers associated with renal injury, as reflected by reduced levels of BUN, Scr, KIM-1, and Cys-C. Transcriptomic analysis revealed significant enrichment of NF-κB signalling in the non-pulsatile group. Angiotensin II (Ang II) expression was significantly higher in the non-pulsatile group and correlated with inflammation. In the non-pulsatile perfusion group, rats receiving captopril exhibited reduced Ang II expression and showed trends towards lower renal injury biomarkers, suppressed inflammatory responses, and decreased NF-κB activation. CONCLUSIONS: These findings in a rat ECLS model suggest that pulsatile perfusion is associated with lower levels of renal injury-related and inflammatory markers compared to non-pulsatile perfusion, potentially involving modulation of Ang II expression. Preliminary observations also indicate that captopril administration under non-pulsatile conditions may be linked to reduced NF-κB activation and inflammatory responses. However, these results are exploratory in nature and require further validation in clinically relevant models.

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