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Kidney Week

Abstract: FR-PO156

Notch Signaling Pathway Mediates Anti-Inflammatory Effects of Vagus Nerve Stimulation

Session Information

  • AKI: Mechanisms - II
    November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Kuwabara, Shuhei, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Nash, William, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Yao, Junlan, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Zheng, Shuqiu, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Okusa, Mark D., University of Virginia School of Medicine, Charlottesville, Virginia, United States

Group or Team Name

  • Division of Nephrology and Center for Immunity, Inflammation, and Regenerative Medicine.
Background

A novel strategy for the prevention and treatment of AKI is activating the cholinergic anti-inflammatory pathway (CAP), a neuroimmune circuit. The CAP can be initiated by vagus nerve stimulation (VNS) and subsequent activation of splenic and peritoneal macrophages (MΦ), leading to suppression of pro-inflammatory cytokine production. We previously showed that an increase in hairy and enhancer of split 1 (Hes1) in peritoneal MΦ contributes to renoprotective effects of CAP. Hes1 is a transcriptional factor, and its expression is regulated by the Notch signaling pathway. However, a direct relationship between the CAP and Notch signaling has been unclear. In the current study, we focused on Notch signaling in MΦ to unravel the detailed molecular mechanism of CAP and to determine the utility of Notch signaling in ameliorating AKI.

Methods

To test if VNS activates Notch signaling in MΦ, we performed VNS before lipopolysaccharide (LPS)-induced AKI. After LPS administration, gene expression of Notch components, cytokines, and Kim-1 was assessed by qPCR. MΦ-specific Notch2 KO mice (Cx3cr1Cre; Notch2fl/fl) and controls (Notch2fl/fl) were subjected to VNS to evaluate whether Notch2 mediates anti-inflammatory responses in MΦ. Flow cytometry analysis was performed to examine the influence of MΦ-specific Notch2 expression on immune cell subpopulations.

Results

VNS suppressed an LPS-induced upregulation of pro-inflammatory cytokines (Tnfa, Il1b, and Ccl2) in MΦ and Kim-1 in kidneys. This event was accompanied by an increase in Notch components including Hes1 in MΦ. After VNS and LPS treatments, BUN levels were increased in Notch2 KO mice, compared to WT controls. Consistently, these Notch2 KO mice showed higher levels of Ccl2 (but not Tnfa and Il1b) and Kim-1 expression in the MΦ and kidneys, respectively. Flow cytometry analysis revealed that under physiological conditions, Notch2 deficiency in MΦ induced a decrease in MΦ and monocyte numbers in the spleen and circulation.

Conclusion

Our findings suggest that: 1) during LPS-induced AKI, Notch2 mediates anti-inflammatory effects of VNS by suppressing Ccl2 expression in MΦ, and 2) Notch2 in MΦ positively regulates cell subpopulations of MΦ and monocytes, which might inhibit neutrophil infiltration into the kidneys and attenuate subsequent injury.

Funding

  • Private Foundation Support