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Kidney Week

Abstract: PO0163

A Vago-Sympathetic Reflex Mediates Kidney Protection from Ischemia-Reperfusion Injury

Session Information

  • AKI Mechanisms - 1
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Tanaka, Shinji, Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia, United States
  • Abe, Chikara, Department of Pharmacology, University of Virginia, Charlottesville, United States
  • Zheng, Shuqiu, Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia, United States
  • Yamaoka, Yusuke, Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, United States
  • Lipsey, Jonathan E., Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia, United States
  • Skrypnyk, Nataliya, Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia, United States
  • Yao, Junlan, Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia, United States
  • Inoue, Tsuyoshi, Division of CKD Pathophysiology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
  • Stornetta, Daniel S., Department of Pharmacology, University of Virginia, Charlottesville, Virginia, United States
  • Abbott, Stephen, Department of Pharmacology, University of Virginia, Charlottesville, Virginia, United States
  • Rosin, Diane L., Department of Pharmacology, University of Virginia, Charlottesville, Virginia, United States
  • Stornetta, Ruth, Department of Pharmacology, University of Virginia, Charlottesville, Virginia, United States
  • Guyenet, Patrice G., Department of Pharmacology, University of Virginia, Charlottesville, Virginia, United States
  • Okusa, Mark D., Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia, United States
Background

We recently showed that electrical stimulation of the cervical vagus nerve (VNS) protected mouse kidneys from ischemia-reperfusion injury (IRI) by activating the cholinergic anti-inflammatory pathway (PMID: 27088805). Whether the protection is caused by the activation of vagal efferent or afferent fibers needs clarification.

Methods

We generated choline acetyltransferase-channelrhodopsin-2 (Chat-ChR2) mice and vesicular glutamate transporter 2 (Vglut2)-ChR2 mice, which express ChR2 in vagal efferent and afferent neurons, respectively. Selective optogenetic stimulation of vagal sensory afferent fibers (Vglut2-ChR2 mice) or efferent fibers (Chat-ChR2 mice) 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 and Vglut2-ChR2 mice as shown by decreased plasma creatinine, reduced renal Kim-1 expression and improved kidney histology. Next, we sought to identify the circuitry responsible for the renal protection elicited by vagal sensory afferent stimulation (afferent VNS). The protective effect of afferent VNS persisted after blocking the rise in corticosterone with mifepristone or after subdiaphragmatic vagotomy, but was abolished by the sympathetic/parasympathetic ganglionic blocker hexamethonium. Moreover, ablation of the splenic nerve (predominantly sympathetic nerve) and splenectomy abolished the protective effect of afferent VNS. Finally, adoptive transfer of splenocytes from mice subjected to afferent VNS, as opposed to sham stimulation, protected recipient mice from kidney IRI, suggesting that splenocytes activated through the splenic nerve mediate the kidney protection.

Conclusion

Stimulation of either vagal efferent or afferent neurons protected the kidneys from IRI. The beneficial effect of afferent VNS requires the spleen and is mediated via a vago-sympathetic reflex.

Funding

  • NIDDK Support