Vagus nerve stimulation even after injury ameliorates cisplatin-induced nephropathy via reducing macrophage infiltration

Abstract

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. 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. Despite the advancements in modern medical technology, acute kidney injury (AKI) is still one of the major comorbidities in hospital settings. It is estimated that AKI occurs in approximately 15% of hospitalized patients and 60% of critically ill patients 1 , and morbidity and mortality rates remain high 2,3. In addition, AKI is a risk factor for chronic kidney disease (CKD) and end-stage renal disease (ESRD) 4. Therefore, prevention of AKI development and progression to CKD is essential. Inflammation plays an important role in the pathogenesis of AKI 5. Moreover, chronic inflammation contributes to the progression of CKD. Therefore, suppression of inflammation plays a potential role in treating kidney injury. Recently, a new anti-inflammatory pathway called the cholinergic anti-inflammatory pathway (CAP) has been discovered 6. The CAP consists of both afferent and efferent arms, and both afferent and efferent vagus nerves play important roles. The afferent vagus nerve conducts inflammatory information from the peripheral organs to the central nervous system. In the brainstem, the afferent vagus nerve activates the C1 neurons, which make a major contribution to the central regulation of autonomic function 7 , and further stimulate the efferent vagus nerve 8. Previously, Inoue and Abe et al. reported that vagus nerve stimulation (VNS) protected the kidney from ischemia-reperfusion injury (IRI) through activation of the CAP 9. Although there are many kinds of inflammatory cells such as B cells, T cells, and dendritic cells ...

Neuroimmune system-mediated renal protection mechanisms

“…The results confirmed that VNS had an organ-protective effect, even post-cisplatin-induced nephropathy, and that CCL2 and CCL11, factors related to immune cell chemotaxis, were suppressed in macrophages through α7nAChR (Fig. 3f) [15].…”

Cholinergic immunomodulation in inflammatory bowel diseases

“…Therefore, activation of vagal efferent signaling by VNS results in activation of the sympathetic innervation and release of norepinephrine (NE) in the spleen. Accordingly, splenectomy reverses VNS protective effects in models of endotoxemia ( Huston et al., 2006 ), nephropathy ( Uni et al., 2020 ), kidney ischemia-reperfusion injury ( Inoue et al., 2016 ) and colitis ( Ji et al., 2014 ) ( Fig. 1 a).…”

Clinical perspectives on vagus nerve stimulation: present and future

“…From a clinical perspective, this study suggested that VNS could be employed prophylactically in situations in which the patient is at high risk of developing AKI. This was followed by a study demonstrating that VNS administered 24 h after cisplatin treatment was protective against kidney injury which was dependent upon the CAP [ 86 ]. Preclinical studies have clearly demonstrated a protective role of VNS in kidney injury and clinical trials are now warranted to determine its therapeutic benefit in patients.…”