1. Activation of the α7nAChR by GTS-21 mitigates septic tubular cell injury and modulates macrophage infiltration.
- Author
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Yang A, Wu CH, Matsuo S, Umene R, Nakamura Y, and Inoue T
- Subjects
- Animals, Humans, Male, Mice, Anti-Inflammatory Agents pharmacology, Anti-Inflammatory Agents therapeutic use, Benzylidene Compounds pharmacology, Benzylidene Compounds therapeutic use, Cell Line, Cytokines metabolism, Disease Models, Animal, Kidney Tubules pathology, Kidney Tubules drug effects, Mice, Inbred C57BL, Pyridines, Acute Kidney Injury drug therapy, Acute Kidney Injury metabolism, Acute Kidney Injury pathology, alpha7 Nicotinic Acetylcholine Receptor metabolism, alpha7 Nicotinic Acetylcholine Receptor agonists, Lipopolysaccharides, Macrophages drug effects, Macrophages immunology, Macrophages metabolism, Sepsis drug therapy, Sepsis complications, Sepsis immunology
- Abstract
The most common and serious complication among hospitalized and critically ill patients is sepsis-associated acute kidney damage (S-AKI), which raises the risk of comorbidities and is linked to a high mortality rate. Cholinergic anti-inflammatory pathway (CAP), an anti-inflammatory pathway mediated by the vagus nerve, acetylcholine, and α7 nicotinic acetylcholine receptors (α7nAChRs), offers new perspectives for the treatment of S-AKI. In this study, we investigated the role of CAP and α7nAChR in kidney injury by employing an LPS-induced septic kidney injury mouse model and GTS-21 intervention. C57BL/6 mice were injected with LPS, with or without GTS-21, in different subgroups. Kidney function was assessed by plasma creatinine, histology, and markers of kidney injury 24 h after intervention. The results demonstrated that GTS-21 could inhibit the systemic inflammatory response and directly protect the tubular cell injury from LPS. To explore the novel gene involved in this response, RNA sequencing of the renal proximal tubular epithelial cell (HK-2), pretreated with LPS and GTS-21, was conducted. The results indicate that GTS-21 administration reduces LPS-induced cytokines and chemokines secretion by HK-2, including CCL20, a potent chemokine attracting monocytes/macrophages. Furthermore, a macrophage transmigration assay revealed that GTS-21 inhibits macrophage transmigration by downregulating the expression of CCL20 in HK-2 cells. In conclusion, GTS-21, as an α7nAChR agonist, emerges as a noteworthy and versatile treatment for S-AKI. Its dual function of directly protecting renal tubular cells and regulating inflammatory responses represents a major advancement in the treatment of sepsis-induced AKI. This finding might pave the way for novel approaches to improving patient outcomes and reducing death rates in sepsis-related complications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)
- Published
- 2024
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