1. Academic Validation
  2. S100-A8/A9 activated TLR4 in renal tubular cells to promote ischemia-reperfusion injury and fibrosis

S100-A8/A9 activated TLR4 in renal tubular cells to promote ischemia-reperfusion injury and fibrosis

  • Int Immunopharmacol. 2023 Apr 5;118:110110. doi: 10.1016/j.intimp.2023.110110.
Jing Huang 1 Lang Shi 1 Yao Xia 2 Jiefu Zhu 3 Hongchu Zha 2 Xiongfei Wu 4 Zhixia Song 5
Affiliations

Affiliations

  • 1 Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
  • 2 Department of Nephrology, The First Clinical Medical College of Three Gorges University, Center People's Hospital of Yichang, Yichang, Hubei 443000, China.
  • 3 Department of Organ transplantation, Renmin Hospital of Wuhan University, Wuhan 430060, China.
  • 4 Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan 430060, China. Electronic address: rm003155@whu.edu.cn.
  • 5 Department of Nephrology, The First Clinical Medical College of Three Gorges University, Center People's Hospital of Yichang, Yichang, Hubei 443000, China. Electronic address: songzhixia@ctgu.edu.cn.
Abstract

Renal ischemia/reperfusion injury (IRI) is a significant clinical problem without effective therapy. Unbiased omics approaches may reveal key renal mediators to initiate IRI. S100-A8/A9 was identified as the most significantly upregulated gene and protein base on proteomic analysis and RNA Sequencing during the early reperfusion stage. S100-A8/A9 levels were significantly increased 1 day after transplantation in patients with donation after brain death (DBD). S100-A8/A9 production was associated with CD11b+Ly6G+ CXCR2+ immunocytes infiltration. Administration of S100-A8/A9 blocker ABR238901 significantly alleviates renal tubular injury, inflammatory cell infiltration, and renal fibrosis after renal IRI. Mechanistically, S100-A8/A9 could promote renal tubular cell injury and profibrotic cytokine production via TLR4. In conclusion, our findings found that early activation of S100-A8/A9 in renal IRI and targeting S100-A8/A9 signaling alleviates tubular injury and inhibits inflammatory response and renal fibrosis, which may provide a novel target for the prevention and treatment of acute kidney injury.

Keywords

Fibrosis; Renal ischemia/reperfusion injury; S100-A8/A9; TLR4 and Proximal tubular epithelial cells.

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