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

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

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 9

Protective effect of adoptively transferred splenocytes from VNS-treated mice requires α7nAChRs.

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Protective effect of adoptively transferred splenocytes from VNS-treated...
α7KO mice and WT (progeny controls) were used as donor mice. Donor mice underwent VNS or sham VNS treatment 1 day before splenocyte transfer. Twenty-four hours later, 1 × 106 splenocytes from donor mice were injected i.v. into the recipient mice (WT). The recipient mice were subjected to IRI 24 hours after the transfer, and plasma creatinine was evaluated 24 hours later. The recipient mice that received splenocytes from VNS-treated WT mice were protected against IRI, but this protection was abolished when the mice received splenocytes from VNS-treated α7KO mice. n = 5 each (n = 4 for PBS-treated group). Data were analyzed using 1-way ANOVA. Means were compared by post hoc multiple-comparison test (Tukey’s). ***P < 0.001.