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

Abstract

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.

The Cholinergic Anti-Inflammatory Pathway Attenuates the Development of Atherosclerosis in Apoe-/- Mice through Modulating Macrophage Functions

“…Via an inflammatory reflex of the CAP, the vagus nerve perceives the peripheral inflammatory signal and then releases the neurotransmitter acetylcholine (Ach), which stimulates alpha 7 nicotinic acetylcholine receptor (α7nAchR) in multiple immune cells such as macrophage, and eventually inhibits the production of pro-inflammatory cytokines and cytokine-related devastating effects [ 6 , 7 , 8 ]. It has been widely studied that the activation of CAP, through stimulating the vagus nerve or activating α7nAchR receptor by a specific cholinergic agonist can effectively attenuate the development of various inflammatory diseases, including endotoxemia, rheumatoid arthritis, ischemia/reperfusion injury, and hemorrhagic shock [ 9 , 10 , 11 , 12 , 13 , 14 ]. Recent studies indicate that CAP may also play a functional role in the regulation of cardiovascular diseases such as atherosclerosis (AS), a chronic inflammatory condition [ 15 , 16 , 17 , 18 ].…”

Cholinergic Elicitation Prevents Ventricular Remodeling via Alleviations of Myocardial Mitochondrial Injury Linked to Inflammation in Ischemia-Induced Chronic Heart Failure Rats

“…The skin was incised along the right cervical line before the blunt dissection of the subcutaneous muscle layer. The right cervical vagal nerve was located in the carotid sheath, meticulously isolated by a glass needle, and cut off with ceramic scissors [ 20 ]. After the vagotomy, the incised skin was closed with interrupted sutures, and the rats were individually housed.…”

Cooling Down Inflammation in the Cardiovascular System via the Nicotinic Acetylcholine Receptor

“…Baroreflex sensitivity is another marker of autonomic function having an important role in long-term development of hypertension. 50,51 Administration of GTS-21 to rats with angiotensin IIinduced hypertension improved baroreflex sensitivity and attenuated BP. Moreover, excessive renal fibrosis and overexpression of inflammatory cytokines were reduced (Fig.…”

“…In vitro investigations revealed that GTS-21 repressed nuclear factor κB (NF-κB) activation, decreased angiotensin II-induced epithelial-–mesenchymal transition, and lowered inflammation and fibrosis in NRK-52E cells. 51 Similar to α7-nAChR agonists, the acetylcholinesterase inhibitor donepezil produced beneficial effects for hypertension. 52 While both donepezil and pyridostigmine were able to improve cardiac vagal tone and prevent cardiac remodeling, only donepezil could reduce high BP and plasma cytokine levels in spontaneously hypertensive rats.…”