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Kidney Week

Abstract: TH-OR015

Optogenetic Stimulation of the Vagus Nerve Identifies Distinct Pathways That Mediate Kidney Protection 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
  • Zheng, Shuqiu, University of Virginia, Charlottesville, Virginia, United States
  • Stornetta, Daniel S., University of virginia, Charlottesville, Virginia, United States
  • Abbott, Stephen, University of virginia, Charlottesville, Virginia, United States
  • Rosin, Diane L., University of virginia, Charlottesville, Virginia, United States
  • Stornetta, Ruth, 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 showed that electrical vagus nerve stimulation (VNS) in the neck protected mouse kidneys from ischemia-reperfusion injury (IRI) by activating the cholinergic anti-inflammatory pathway (CAP) (PMID: 27088805). Stimulation of vagal efferent neurons is believed to be essential in the activation of CAP. However, electrical stimulation of the cervical vagus nerve excites both the efferent (motor) and afferent (sensory) neurons. It is still unclear which pathway is important in ameliorating kidney injury.

Methods

Channelrhodopsin-2 (ChR2) is a light-sensitive, non-selective cation channel; the gate is opened only during blue light application. We generated choline acetyltransferase (Chat)-ChR2 mice and vesicular glutamate transporter 2 (Vglut2)-ChR2 mice, which express ChR2 in vagal efferent and afferent neurons, respectively. Thus, when the cervical vagus nerve is illuminated with blue laser, vagal efferent and afferent neurons are selectively stimulated in Chat-ChR2 and Vglut2-ChR2 mice, respectively. For selective ablation of C1 neurons, which are a group of lower brainstem catecholaminergic/glutamatergic neurons, AAV2-flex-taCasp3-TEVp was injected bilaterally into the rostral ventrolateral medulla (the area where C1 neurons are localized) of dopamine beta-hydroxylase (Dbh)-Cre mice 6 weeks before electrical afferent/efferent VNS. Optogenetic VNS with blue laser or electrical VNS was performed 24 h before bilateral renal IRI, and mice were euthanized 24 h after IRI.

Results

Optogenetic VNS protected kidneys from IRI in both Chat-ChR2 mice (pCr: 1.53±0.20 vs. 0.48±0.05 mg/dL) and Vglut2-ChR2 mice (pCr: 1.09±0.22 vs. 0.44±0.06 mg/dL), which was supported by improved kidney histology and decreased renal Kim-1 expression in the VNS groups. Next, based on our recent study (PMID: 28288124), we hypothesized that the C1 neurons mediate the afferent VNS pathway. Electrical VNS significantly increased the number of cFos-positive C1 neurons, and selective ablation of C1 neurons eliminated the protective effect of afferent VNS, but not efferent VNS.

Conclusion

Both stimulation of vagal efferent and afferent neurons protected the kidneys from IRI. C1 neurons in the lower brainstem were involved in the protective pathway elicited by afferent VNS.

Funding

  • NIDDK Support