Examining the Anti-inflammatory and Renoprotective Effects Resulting from Parasympathetic Nerve Stimulation after Inflammation

Background: Recent reports have indicated that pre-injury stimulation of the parasympathetic nervous system, activating the cholinergic anti-inflammatory pathway (CAP), yields anti-inflammatory and renoprotective effects. However, it is unclear whether similar effects can be achieved with post-injury stimulation of the parasympathetic nervous system. This study aims to confirm whether post-inflammatory stimulation of the parasympathetic nervous system can indeed lead to anti-inflammatory and renoprotective effects, as well as to elucidate the underlying mechanisms. Methods: The animal model employed in this study involved inducing acute kidney injury/sepsis using lipopolysaccharide (LPS). Due to concerns about the highly invasive nature of direct vagus nerve stimulation, we chose to activate the parasympathetic nervous system by administering 3-(2,4-Dimethoxybenzylidene)-anabaseine dihydrochloride (GTS-21), a selective α7 nicotinic acetylcholine receptor agonist. After inducing inflammation in wild-type C57BL/6 mice by administering LPS, we subsequently administered GTS-21 to evaluate its anti-inflammatory and renal protective effects. Furthermore, we induced inflammation in RAW 264 (mouse macrophages) and U937 (human macrophages) using LPS, followed by parasympathetic nerve stimulation, to evaluate their anti-inflammatory effects similarly. Furthermore, we conducted RNA-seq analyses on each cell type to elucidate the underlying molecular mechanisms. Results: We confirmed that administering the selective α7 nicotinic acetylcholine receptor agonist, GTS-21, in the mouse model of acute kidney injury/sepsis induced by LPS, resulted in anti-inflammatory and renal protective effects. Moreover, based on the findings from RNA-Seq analysis, we elucidated that the expression of CCL2, a chemokine, in splenic macrophages is involved in mediating these effects. Conclusion: Even after inflammation induction, stimulation of the parasympathetic nervous system yielded anti-inflammatory and renoprotective effects. This discovery holds significant promise for the development of novel treatments for sepsis and AKI.