Activation of the Cholinergic Anti-inflammatory Pathway Attenuated Angiotension II-Dependent Hypertension and Renal Injury

Background: Angiotensin II (AngII) induces renal fibrosis, characterized by fibroblast proliferation, inflammatory cell infiltration and excessive extracellular matrix deposition, all of which was relevant closely to hypertension. The vagus nerve-related cholinergic anti-inflammatory pathway (CAP) modulates local and systemic inflammatory responses. The aim of present study was to determine the effect of CAP on renal inflammation and fibrosis. Methods and Results: AngII-induced hypertension was induced in vivo by 14-days low-dose AngII infusion from osmotic minipumps. We used GTS-21 dihydrochloride, a selective nicotinic acetylcholine receptor agonist. Daily intraperitoneal GTS-21 injection and/or vagotomy started after hypertension was confirmed and continued for 4 weeks. The elevated blood pressure caused by AngII was significantly attenuated by GTS-21. Improved baroreflex sensitivity was observed after GTS-21 administration. Masson stain and immunoblotting revealed that deposition of excessive fibrosis and overexpression of inflammatory cytokines induced by AngII was reduced by GTS-21. To determine the role of autonomic control in CAP, unilateral vagotomy was performed. Vagotomy weakened the effect of CAP on AngII-induced hypertension. In vitro, GTS-21 suppressed NF-κB activation, attenuated AngII-induced epithelial-mesenchymal transition and reduced inflammation and fibrosis in NRK-52E cells; α-bungarotoxin (α-Bgt, an α7-nAChR selective antagonist) partly inhibited these effects. Conclusion: CAP protected against AngII-induced hypertension via improvement in autonomic control, suppression of NF-κB activation, and reduction of renal fibrosis and inflammatory response.