2. Academic Validation
  3. S100A2 activation promotes interstitial fibrosis in kidneys by FoxO1-mediated epithelial-mesenchymal transition

S100A2 activation promotes interstitial fibrosis in kidneys by FoxO1-mediated epithelial-mesenchymal transition

  • Cell Biol Toxicol. 2024 Oct 9;40(1):86. doi: 10.1007/s10565-024-09929-7.
Xuejia Yang # 1,  Fan Zheng # 1,  Penghua Yan # 2,  Xueting Liu 3,  Xuanwen Chen 3,  Xinyu Du 3,  Yin Zhang 4,  Peilei Wang 4,  Chaosheng Chen 5 6,  Hong Lu 7,  Yongheng Bai 8 9
Affiliations

Affiliations

  • 1 Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China.
  • 2 Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China.
  • 3 Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China.
  • 4 Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China.
  • 5 Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China. wz_ccs8@163.com.
  • 6 Institute of Chronic Nephropathy, Wenzhou Medical University, Wenzhou, 325035, China. wz_ccs8@163.com.
  • 7 Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China. luhonglisa@163.com.
  • 8 Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China. wzbyh@wmu.edu.cn.
  • 9 Institute of Chronic Nephropathy, Wenzhou Medical University, Wenzhou, 325035, China. wzbyh@wmu.edu.cn.
  • # Contributed equally.
PMID: 39382800 DOI: 10.1007/s10565-024-09929-7
Abstract

Background: Renal interstitial fibrosis (RIF) is a common feature of chronic kidney diseases (CKD), with epithelial-mesenchymal transition (EMT) being one of its important mechanisms. S100A2 is a protein associated with cell proliferation and differentiation, but its specific functions and molecular mechanisms in RIF remain to be determined.

Methods: S100A2 levels were evaluated in three mouse models, including unilateral ureteral obstruction (UUO), ischemia-reperfusion injury (IRI), and aristolochic acid nephropathy (AAN), as well as in TGF-β1- treated HK-2 cells and in kidney tissue samples. Furthermore, the role of S100A2 and its interaction with FoxO1 was investigated using RT-qPCR, immunoblotting, immunofluorescence staining, co-immunoprecipitation (Co-IP), transcriptome Sequencing, and gain- or loss-of-function approaches in vitro.

Results: Elevated expression levels of S100A2 were observed in three mouse models and TGF-β1-treated HK2 cells, as well as in kidney tissue samples. Following siRNA silencing of S100A2, exposure to TGF-β1 in cultured HK-2 cells suppressed EMT process and extracellular matrix (ECM) accumulation. Conversely, Overexpression of S100A2 induced EMT and ECM deposition. Notably, we identified that S100A2-mediated EMT depends on FoxO1. Immunofluorescence staining indicated that S100A2 and FoxO1 colocalized in the nucleus and cytoplasm, and their interaction was verified in Co-IP assay. S100A2 knockdown decreased TGF-β1-induced phosphorylation of FoxO1 and increased its protein expression, whereas S100A2 overexpression hampered FoxO1 activation. Furthermore, pharmacological blockade of FoxO1 rescued the induction of TGF-β1 on EMT and ECM deposition in S100A2 siRNA-treated cells.

Conclusion: S100A2 activation exacerbates interstitial fibrosis in kidneys by facilitating FoxO1-mediated EMT.

Keywords

ECM; EMT; FoxO1; RIF; S100A2.

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