α7nAChR agonist GTS-21 ameliorates sepsis-induced acute kidney injury via MEF2/PGC-1α/HO-1 axis in mice

Abstract

Background: Sepsis-induced acute kidney injury (S-AKI) is a major global public health concern, yet effective therapeutic strategies remain limited. Mitochondrial dysfunction in renal tissues is a key pathogenic mechanism underlying S-AKI. GTS-21, a selective α7 nicotinic acetylcholine receptor (α7nAChR) agonist, exhibits anti-inflammatory and renoprotective effects in S-AKI.

Methods: We investigated the role of α7nAChR in S-AKI using both in vitro (lipopolysaccharide (LPS)-induced renal tubular cell injury) and in vivo (caecal ligation and puncture (CLP)-induced septic mice) models, with GTS-21 treatment.

Results: GTS-21 significantly attenuated mitochondrial dysfunction, suppressed apoptosis, and alleviated inflammation, thereby protecting renal tubular cells and renal tissues against LPS- and CLP-induced injury. Mechanistically, GTS-21 activated α7nAChR and upregulated myocyte enhancer factor 2 (MEF2), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and heme oxygenase-1 (HO-1), which collectively mediate its anti-oxidative, anti-apoptotic and anti-inflammatory effects.

Conclusion: These findings suggest that GTS-21 may represent a potential therapeutic strategy for sepsis-induced kidney injury.

Keywords

α7nAChR / HO-1 / MEF2 / mitochondria / PGC-1α / sepsis-induced acute kidney injury

References

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2026 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.