2. Academic Validation
  3. TGR5 rescues renal ischemia-reperfusion injury by suppressing ferroptosis and cAMP/PKA/Nrf2 axis

TGR5 rescues renal ischemia-reperfusion injury by suppressing ferroptosis and cAMP/PKA/Nrf2 axis

  • Eur J Pharmacol. 2026 Feb 15:1015:178597. doi: 10.1016/j.ejphar.2026.178597.
Suhan Zhou 1,  Honghong Wang 1,  Huanhuan Zhu 1,  Shilong Xiang 1,  Minjing Zhang 2,  Meifang Wang 1,  Weilian Feng 3,  Guizhen Yu 1,  Bingjue Li 1,  Fanghao Cai 1,  Jingyi Zhou 1,  Zheng Li 1,  Runzhi Zhu 2,  Xiang Yan 2,  Jianghua Chen 1,  En Yin Lai 4,  Gensheng Zhang 5,  Fei Han 6
Affiliations

Affiliations

  • 1 Kidney Disease Center, The First Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, Hangzhou, 310003, Zhejiang, China; Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, 310003, Zhejiang, China.
  • 2 Department of Urology, Pediatric Urolith Center, Pediatric Nephrology & Urology Medical Research Center, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, Zhejiang, China.
  • 3 Ultrasound Medicine Department, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China.
  • 4 Kidney Disease Center, The First Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, Hangzhou, 310003, Zhejiang, China; Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, 310003, Zhejiang, China. Electronic address: [email protected].
  • 5 Department of Urology, Pediatric Urolith Center, Pediatric Nephrology & Urology Medical Research Center, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, Zhejiang, China. Electronic address: [email protected].
  • 6 Kidney Disease Center, The First Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, Hangzhou, 310003, Zhejiang, China; Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, 310003, Zhejiang, China. Electronic address: [email protected].
PMID: 41587732 DOI: 10.1016/j.ejphar.2026.178597
Abstract

Background: Emerging evidence highlights the critical role of Ferroptosis in the pathophysiology of both acute kidney injury (AKI) and chronic kidney disease (CKD). Nuclear factor erythroid 2-related factor 2 (Nrf2), which is activated through pathways involving Takeda G protein-coupled receptor 5 (TGR5), has emerged as a potential therapeutic target to inhibit Ferroptosis.

Methods: We evaluated kidney TGR5 expression and urinary TGR5 excretion in AKI patients, as well as in vivo (mouse) and in vitro (cellular) models of AKI induced by ischemia-reperfusion (IR) injury and subsequent CKD. Correlation analyses were conducted with renal function markers. Cellular injury models were established using human renal proximal tubular epithelial cells (HK-2) and human umbilical vein endothelial cells (HUVECs). The TGR5 agonist INT-777 was used to activate TGR5 signaling. Morphological changes in kidney tissues and cells were examined by transmission electron microscopy, and intracellular ferrous iron (Fe2+) levels, Reactive Oxygen Species (ROS), and malondialdehyde (MDA) were quantified with commercial assay kits.

Results: Decreased kidney TGR5 expression and increased urinary TGR5 excretion were observed in AKI patients and experimental models, both correlating significantly with impaired renal function. Importantly, treatment with the TGR5 agonist INT-777 activated the TGR5/cAMP/PKA/Nrf2 pathway, suppressed oxidative stress and Ferroptosis, and thereby attenuated synchronous injury in tubular epithelial and endothelial cells.

Conclusions: This study offers novel insights into Ferroptosis mechanisms in AKI and subsequent CKD, identifying TGR5 as a promising therapeutic target.

Keywords

Acute kidney injury; Ferroptosis; Ischemia-reperfusion; Takeda G protein-coupled receptor 5.

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