Notch signaling pathway mediates anti-inflammatory effects of vagus nerve stimulation during lipopolysaccharide-induced acute kidney injury.

Summary

In LPS-induced AKI, vagus nerve stimulation enhanced macrophage Notch2 signaling, reduced splenic inflammation and renal tissue injury, and upregulated transferrin linked to iron homeostasis. Macrophage-specific Notch2 knockout blunted these protective effects, implicating Notch2 as a key mediator of the cholinergic anti-inflammatory pathway.

Key Findings

• Vagus nerve stimulation enhanced macrophage Notch2 signaling in LPS-induced AKI, reducing splenic inflammation and renal tissue damage.
• Macrophage-specific Notch2 knockout attenuated the anti-inflammatory and organ-protective effects of VNS.
• VNS and macrophage Notch2 signaling upregulated transferrin, suggesting protection via iron homeostasis.
• Findings mechanistically link the cholinergic anti-inflammatory pathway to Notch signaling in sepsis-related AKI.

Clinical Implications

While preclinical, the Notch2–CAP axis and transferrin upregulation nominate testable targets for sepsis-associated AKI, and support clinical translation of vagus nerve stimulation or pharmacologic Notch modulators in carefully designed trials.

Limitations

• Murine LPS model may not capture full complexity of human polymicrobial sepsis or AKI phenotypes.
• Translational efficacy, dosing, and safety of VNS or Notch modulation in humans remain untested.

Future Directions

Test the Notch2–CAP axis in polymicrobial (e.g., CLP) models and evaluate VNS parameters; assess pharmacologic Notch modulation and transferrin/iron-targeted strategies; design early-phase clinical trials in SA-AKI.