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Kidney Week

Abstract: TH-PO126

Optogenetic Stimulation of Either Efferent or Afferent Vagus Neurons Protects Kidneys from Ischemia-Reperfusion Injury

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Tanaka, Shinji, University of Virginia, Charlottesville, Virginia, United States
  • Abe, Chikara, University of Virginia, Charlottesville, United States
  • Rosin, Diane L., University of Virginia, Charlottesville, Virginia, United States
  • Guyenet, Patrice G., University of Virginia, Charlottesville, Virginia, United States
  • Okusa, Mark D., University of Virginia, Charlottesville, Virginia, United States
Background

We recently reported that electrical vagus nerve stimulation (VNS) in the neck protects mouse kidneys from ischemia-reperfusion injury (IRI) by activating the cholinergic anti-inflammatory pathway (CAP). Stimulation of vagal efferent neurons is believed to be essential to the activation of CAP. However, we found that electrical stimulation of the cephalic end of a divided vagus nerve was equally effective against IRI. It is therefore still unclear whether afferent or efferent VNS is most important in ameliorating renal IRI.

Methods

Channelrhodopsin-2 (ChR2) is a light-sensitive, non-selective cation channel that is opened only during blue light application. We crossed loxP-STOP-loxP ChR2 mice with choline acetyltransferase (Chat)-cre and vesicular glutamate transporter 2 (Vglut2)-cre mice to generate Chat-ChR2 and Vglut2-ChR2 mice expressing ChR2 in vagal efferent and afferent neurons, respectively. Illumination of the cervical vagus nerve with blue laser selectively stimulated vagal efferent and afferent neurons (“efferent VNS” and “afferent VNS”) in Chat-ChR2 and Vglut2-ChR2 mice, respectively. Optogenetic stimulation with blue laser (wavelength: 473 nm) of left cervical vagus nerve was performed with 50 Hz (10 sec) to observe physiological changes and with 5 Hz (10 min) in renal IRI experiments to minimize physiological changes. IRI surgery was performed 24 h after optogenetic VNS; mice were euthanized 24 h later.

Results

Blue laser (50 Hz) applied to the cervical vagus nerve, decreased heart rate markedly (300→180 bpm) with no change in respiratory rate in Chat-ChR2 mice and completely paused breathing by activation of Hering-Breuer inflation reflex in Vglut2-ChR2 mice, proving selective efferent VNS and afferent VNS. Both efferent VNS (plasma Cr: 1.53±0.20 vs. 0.48±0.05 mg/dL) and afferent VNS (plasma Cr: 1.09±0.22 vs. 0.44±0.06 mg/dL) with 5 Hz protected kidneys from IRI, improved kidney histology and decreased renal Kim-1 expression. Splenectomy abolished the protective effect in both groups.

Conclusion

Afferent VNS as well as efferent VNS protects the kidneys from IRI. In both cases protection requires the spleen. These results support the hypothesis that CAP underlies the beneficial effect of efferent VNS on IRI and propose that a sympathetic reflex mediates the protective effect of afferent VNS.

Funding

  • NIDDK Support