RRC ID 81328
Author Yang A, Wu CH, Matsuo S, Umene R, Nakamura Y, Inoue T.
Title Activation of the α7nAChR by GTS-21 mitigates septic tubular cell injury and modulates macrophage infiltration.
Journal Int Immunopharmacol
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.
Volume 138
Pages 112555
Published 2024-9-10
DOI 10.1016/j.intimp.2024.112555
PII S1567-5769(24)01076-2
PMID 38943973
MeSH Acute Kidney Injury* / drug therapy Acute Kidney Injury* / metabolism Acute Kidney Injury* / pathology Animals Anti-Inflammatory Agents / pharmacology Anti-Inflammatory Agents / therapeutic use Benzylidene Compounds / pharmacology Benzylidene Compounds / therapeutic use Cell Line Cytokines / metabolism Disease Models, Animal Humans Kidney Tubules / drug effects Kidney Tubules / pathology Lipopolysaccharides* Macrophages* / drug effects Macrophages* / immunology Macrophages* / metabolism Male Mice Mice, Inbred C57BL Pyridines Sepsis* / complications Sepsis* / drug therapy Sepsis* / immunology alpha7 Nicotinic Acetylcholine Receptor* / agonists alpha7 Nicotinic Acetylcholine Receptor* / metabolism
Resource
Human and Animal Cells RAW 264(RCB0535)