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Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes
Tsuyoshi Inoue, … , Patrice G. Guyenet, Mark D. Okusa
Tsuyoshi Inoue, … , Patrice G. Guyenet, Mark D. Okusa
Published April 18, 2016
Citation Information: J Clin Invest. 2016;126(5):1939-1952. https://doi.org/10.1172/JCI83658.
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Research Article Nephrology

Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes

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Abstract

The nervous and immune systems interact in complex ways to maintain homeostasis and respond to stress or injury, and rapid nerve conduction can provide instantaneous input for modulating inflammation. The inflammatory reflex referred to as the cholinergic antiinflammatory pathway regulates innate and adaptive immunity, and modulation of this reflex by vagus nerve stimulation (VNS) is effective in various inflammatory disease models, such as rheumatoid arthritis and inflammatory bowel disease. Effectiveness of VNS in these models necessitates the integration of neural signals and α7 nicotinic acetylcholine receptors (α7nAChRs) on splenic macrophages. Here, we sought to determine whether electrical stimulation of the vagus nerve attenuates kidney ischemia-reperfusion injury (IRI), which promotes the release of proinflammatory molecules. Stimulation of vagal afferents or efferents in mice 24 hours before IRI markedly attenuated acute kidney injury (AKI) and decreased plasma TNF. Furthermore, this protection was abolished in animals in which splenectomy was performed 7 days before VNS and IRI. In mice lacking α7nAChR, prior VNS did not prevent IRI. Conversely, adoptive transfer of VNS-conditioned α7nAChR splenocytes conferred protection to recipient mice subjected to IRI. Together, these results demonstrate that VNS-mediated attenuation of AKI and systemic inflammation depends on α7nAChR-positive splenocytes.

Authors

Tsuyoshi Inoue, Chikara Abe, Sun-sang J. Sung, Stefan Moscalu, Jakub Jankowski, Liping Huang, Hong Ye, Diane L. Rosin, Patrice G. Guyenet, Mark D. Okusa

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Figure 1

Optimization of VNS.

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Optimization of VNS.
BP and HR were recorded while mice underwent left o...
BP and HR were recorded while mice underwent left or right VNS at constant frequency (5 Hz), but with varied current (10, 30, and 50 μA). Average change in mean arterial BP (A) and HR (B) during vagal stimulation compared with conditions without vagal stimulation. 50 μA stimulation decreased HR significantly. (C and D) Recording of the right vagus efferent nerve during the left VNS. (C) Representative example of right vagus efferent nerve activity (VNA) during left VNS (5 Hz, 1 ms, 50 μA, 10 minutes). Representative data of 3 independent experiments. rVNA, rectified vagus efferent nerve activity. (D) Stimulus-triggered rectified vagus efferent nerve activity was averaged (3,000 sweeps). Arrow indicates stimulation. The latency of the evoked potential is about 20 ms. (E) Mice underwent VNS or sham stimulation (no VNS) surgery 24 hours prior to LPS (10 μg/ml infused at the rate of 10 μl/h for 3 hours) or saline administration, and blood was collected at the end of the infusion period. VNS treatment 24 hours before LPS administration suppressed the LPS-induced increase in circulating TNF. n = 6 each in A and B and n = 5 in E. Data in A and B were analyzed using 2-way ANOVA, and data in E were analyzed using 1-way ANOVA. Means were compared by post hoc multiple-comparison test (Tukey’s). ***P < 0.001.
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