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Kidney Week

Abstract: PO0214

GTS-21 Attenuates the Inflammation of AKI Independent of α7 Nicotinic Acetylcholine Receptor

Session Information

  • AKI Mechanisms - 2
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Nakamura, Yasuna, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
  • Inoue, Tsuyoshi, Nagasaki University School of Medicine Graduate School of Biomedical Sciences, Nagasaki, Nagasaki, Japan
  • Uni, Rie, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
  • Fukaya, Daichi, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
  • Hasegawa, Sho, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
  • Nangaku, Masaomi, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
  • Inagi, Reiko, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
Background

Vagus nerve stimulation protects from kidney injury by activating the cholinergic inflammatory pathway (CAP). It is considered that α7 nicotinic acetylcholine receptor (α7nAChR) in splenic macrophages are important for CAP activation. To elucidate the mechanism of receptor signaling, we promoted further experiments using macrophage-specific α7nAChR knockout mice.

Methods

We generated macrophage-specific α7nAChR-deficient mice by crossbreeding LysM-Cre and α7nAChR flox mice.In vivo, GTS-21 (an α7nAChR specific agonist) was intraperitoneally injected to either wild type C57BL/6J mice (WT) or macrophage-specific α7nAChR-deficient mice prior to administration of lipopolysaccaride (LPS). 4 hours after LPS administration, the mice were euthanized and, plasma TNF-α level, plasma creatinine, BUN were evaluated.
In vitro, murine macrophage cell line RAW264.7 and primary peritoneal macrophages from either WT or α7nAChR-deficient mice were used. These cells were stimulated with LPS after nicotine (pan nicotinic acetylcholine receptor agonist) or GTS-21 was administrated, then TNF-α level was evaluated 4 hours later.

Results

GTS-21 protected the kidney and suppressed the increase of plasma TNF-α induced by LPS in WT mice. Surprisingly GTS-21 decreased plasma TNF-α level induced by LPS in not only WT mice but also macrophage-specific α7nAChR-deficient mice. In vitro experiments, GTS-21 or nicotine treatment suppressed TNF-α induction by LPS in RAW264.7 cells or peritoneal macrophages from WT mice. Furthermore, nicotine also suppressed the induction of TNF-α by LPS even in peritoneal macrophages from α7nAChR-deficient mice.

Conclusion

These results suggest that nicotine or GTS-21 might suppress the inflammation independent of α7nAChR in macrophages in vivo and in vitro.