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

  • Clin Transl Med. 2026 Jul;16(7):e70726. doi: 10.1002/ctm2.70726.
Yu-Jia Tang  1 ,  Hui-Ying Liu  1 ,  Na-Qi Li  2 ,  Xin Zhang  3  4 ,  Yi-Lu Lin  1 ,  Yan Zhang  1 ,  Yao Li  1 ,  Jia-Le Deng  1 ,  Pei-Lin Yang  1 ,  Qing-Min Meng  5 ,  Yi-Jin Tang  5 ,  Zi-Yue Zhang  5 ,  Si-Han Guan  2 ,  Kai Kang  5 ,  Hong-Liang Wang  3 ,  Yang Gao  1
Affiliations
  • 1. Department of Critical Care Medicine, The Sixth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China.
  • 2. Department of Nephrology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China.
  • 3. Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China.
  • 4. Department of Critical Care Medicine, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China.
  • 5. Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China.
PMID: 42333777 DOI: 10.1002/ctm2.70726
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
HO‐1; MEF2; PGC‐1α; mitochondria; sepsis‐induced acute kidney injury; α7nAChR.
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