Abstract
The efficacy of prior activation of an anti-inflammatory pathway called the cholinergic anti-inflammatory pathway (CAP) through vagus nerve stimulation (VNS) has been reported in renal ischemia-reperfusion injury models. However, there have been no reports that have demonstrated the effectiveness of VNS after injury. We investigated the renoprotective effect of VNS in a cisplatin-induced nephropathy model. C57BL/6 mice were injected with cisplatin, and VNS was conducted 24 hours later. Kidney function, histology, and a kidney injury marker (Kim-1) were evaluated 72 hours after cisplatin administration. To further explore the role of the spleen and splenic macrophages, key players in the CAP, splenectomy, and adoptive transfer of macrophages treated with the selective α7 nicotinic acetylcholine receptor agonist GTS-21 were conducted. VNS treatment significantly suppressed cisplatin-induced kidney injury. This effect was abolished by splenectomy, while adoptive transfer of GTS-21-treated macrophages improved renal outcomes. VNS also reduced the expression of cytokines and chemokines, including CCL2, which is a potent chemokine attracting monocytes/macrophages, accompanied by a decline in the number of infiltrating macrophages. Taken together, stimulation of the CAP protected the kidney even after injury in a cisplatin-induced nephropathy model. Considering the feasibility and anti-inflammatory effects of VNS, the findings suggest that VNS may be a promising therapeutic tool for acute kidney injury.
Highlights
The efficacy of prior activation of an anti-inflammatory pathway called the cholinergic antiinflammatory pathway (CAP) through vagus nerve stimulation (VNS) has been reported in renal ischemia-reperfusion injury models
The plasma creatinine and blood urea nitrogen (BUN) levels were not significantly elevated 24 hours after cisplatin injection (Supplementary Figure 1a,b), histology demonstrated the early stage of tubular injury characterized by degenerative changes of proximal tubules (Supplementary Fig. 1c,d)
The expression of kidney injury molecule-1 (Kim-1) and neutrophil gelatinase-associated lipocalin (Ngal) mRNA were elevated in the cisplatin group compared to the control group (Supplementary Fig. 1e,f)
Summary
The efficacy of prior activation of an anti-inflammatory pathway called the cholinergic antiinflammatory pathway (CAP) through vagus nerve stimulation (VNS) has been reported in renal ischemia-reperfusion injury models. VNS treatment significantly suppressed cisplatin-induced kidney injury. This effect was abolished by splenectomy, while adoptive transfer of GTS-21-treated macrophages improved renal outcomes. Stimulation of the CAP protected the kidney even after injury in a cisplatin-induced nephropathy model. Inoue and Abe et al reported that vagus nerve stimulation (VNS) protected the kidney from ischemia-reperfusion injury (IRI) through activation of the CAP9. A pilot study demonstrated that noninvasive VNS downregulated inflammatory cytokine release in healthy subjects[16] These results reinforce the fact that VNS is safe and readily applicable in hospital settings. Given the high prevalence of AKI and the difficulty of identifying patients who will develop AKI, it would be more beneficial if VNS has therapeutic effect, even after injury
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