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Peer-reviewedCC BY-NC-ND 4.0Communications Biology

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

  • Shuhei Kuwabara1,2
  • Hiro Inoue1
  • William T. Nash1
  • Junlan Yao1
  • Vikram Sabapathy1
  • Shuqiu Zheng1
  • Rahul Sharma1
  • Ryo Hatano2
  • Takashi Miki2,3
  • Mark D. Okusa1
  1. 1Division of Nephrology and Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, VA USA
  2. 2Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba, Japan
  3. 3Research Institute of Disaster Medicine (RIDM), Chiba University, Chiba, Japan
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Abstract

The cholinergic anti-inflammatory pathway (CAP) plays a central role in neuroimmunomodulation, and its activation is a potential strategy for ameliorating sepsis-associated acute kidney injury (SA-AKI). However, further investigations are necessary to understand the molecular mechanisms of CAP activation and develop therapies for SA-AKI. Here, we tested whether the Notch signaling pathway, which regulates cell-cell interactions, mediates the anti-inflammatory effects of CAP. Using a mouse model of lipopolysaccharide (LPS)-induced AKI, we found that CAP activation by vagus nerve stimulation (VNS) enhanced Notch2 signaling in macrophages, mitigating inflammation in the spleen and tissue damage in the kidneys. Consistently, macrophage-specific knockout of Notch2 resulted in an attenuation of these anti-inflammatory effects of VNS. We also demonstrated that VNS and macrophage-specific Notch2 signaling might upregulate transferrin, which maintains iron homeostasis, thereby protecting the kidneys. Taken together, our findings suggest the involvement of Notch signaling in the mechanisms of VNS-mediated CAP activation during LPS-induced AKI.

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Cite

BibTeXRIS
BibTeX
@article{kuwabara2026notch,
  title = {{Notch signaling pathway mediates anti-inflammatory effects of vagus nerve stimulation during lipopolysaccharide-induced acute kidney injury}},
  author = {Shuhei Kuwabara and Hiro Inoue and William T. Nash and Junlan Yao and Vikram Sabapathy and Shuqiu Zheng and Rahul Sharma and Ryo Hatano and Takashi Miki and Mark D. Okusa},
  journal = {Communications Biology},
  year = {2026},
  month = jul,
  doi = {10.1038/s42003-026-10620-2},
  url = {https://doi.org/10.1038/s42003-026-10620-2},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Notch signaling pathway mediates anti-inflammatory effects of vagus nerve stimulation during lipopolysaccharide-induced acute kidney injury
AU  - Shuhei Kuwabara
AU  - Hiro Inoue
AU  - William T. Nash
AU  - Junlan Yao
AU  - Vikram Sabapathy
AU  - Shuqiu Zheng
AU  - Rahul Sharma
AU  - Ryo Hatano
AU  - Takashi Miki
AU  - Mark D. Okusa
PY  - 2026
DA  - 2026/07/07
JO  - Communications Biology
DO  - 10.1038/s42003-026-10620-2
UR  - https://doi.org/10.1038/s42003-026-10620-2
AB  - The cholinergic anti-inflammatory pathway (CAP) plays a central role in neuroimmunomodulation, and its activation is a potential strategy for ameliorating sepsis-associated acute kidney injury (SA-AKI). However, further investigations are necessary to understand the molecular mechanisms of CAP activation and develop therapies for SA-AKI. Here, we tested whether the Notch signaling pathway, which regulates cell-cell interactions, mediates the anti-inflammatory effects of CAP. Using a mouse model of lipopolysaccharide (LPS)-induced AKI, we found that CAP activation by vagus nerve stimulation (VNS) enhanced Notch2 signaling in macrophages, mitigating inflammation in the spleen and tissue damage in the kidneys. Consistently, macrophage-specific knockout of Notch2 resulted in an attenuation of these anti-inflammatory effects of VNS. We also demonstrated that VNS and macrophage-specific Notch2 signaling might upregulate transferrin, which maintains iron homeostasis, thereby protecting the kidneys. Taken together, our findings suggest the involvement of Notch signaling in the mechanisms of VNS-mediated CAP activation during LPS-induced AKI.
SN  - 2399-3642
ER  -