Effects of Transauricular Vagus Nerve Stimulation Against Kidney and Spleen Injury in an Experimental Hepatic Ischemia/Reperfusion Model

Abstract

Objective: Hepatic ischemia-reperfusion (I/R) injury leads not only to localized liver dysfunction but also to remote organ injury involving the kidneys and spleen, substantially contributing to high clinical morbidity and mortality. This study aimed to investigate the protective effects of non-invasive transauricular vagus nerve stimulation (tVNS) against secondary kidney and spleen injury in a standardized rat model of hepatic I/R.
Methods: Twenty-one male Sprague-Dawley rats were randomly assigned to three experimental groups (n=7 each): Sham Control (laparotomy with inactive tVNS electrodes), I/R (1-hour partial hepatic ischemia followed by 3-hour reperfusion), and I/R + tVNS (1-hour ischemia + 3-hour reperfusion with simultaneous active tVNS at 1 mA, 20 Hz). Following the reperfusion period, kidney and spleen tissues were harvested. Objective, blinded histopathological evaluations and quantitative image analysis were paired with biochemical assays for oxidative stress and inflammatory markers.
Results: Blinded histological analysis demonstrated that tVNS significantly attenuated I/R-induced pathological damage, including glomerular matrix expansion and tissue congestion. In renal tissues, active tVNS significantly increased total antioxidant status (TAS) (p<0.05), while significantly reducing total oxidant status (TOS) and the oxidative stress index (OSI) (p<0.05 and p<0.01, respectively) compared to the untreated I/R group. Furthermore, renal downstream inflammatory markers IL-1β and hypoxia-inducible factor-1α (HIF-1α) were markedly suppressed by tVNS (p<0.01 and p<0.001, respectively). In splenic tissues, tVNS treatment similarly led to a significant decrease in TOS and OSI levels (p<0.05 and p<0.01, respectively), which was accompanied by a robust reduction in IL-1β expression (p<0.01).
Conclusions: Our findings demonstrate that tVNS exerts systemic protective effects by mitigating hepatic I/R-induced remote tissue injury in both the kidneys and spleen. This neuro-modulatory approach significantly improved antioxidant capacity suppressed tissue hypoxia signaling via HIF-1α, and modulated local inflammatory cytokine cascades. These results suggest that non-invasive tVNS serves as a promising therapeutic strategy to alleviate I/R-related secondary organ damage through the activation of anti-inflammatory pathways.

Keywords

• Ischemia-reperfusion
• Kidney injury
• Splenic congestion
• Vagus nerve stimulation
• Transauricular neuromodulation
• Rat model

Ethical Statement

Experimental protocols were approved by the Animal Ethics Committee of the University of Health Sciences (Approval No: 06/02, 16.10.2024), in accordance with EU Directive 2010/63/EU.

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