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
  • 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. [email protected].
  • 6. Institute of Chronic Nephropathy, Wenzhou Medical University, Wenzhou, 325035, China. [email protected].
  • 7. Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China. [email protected].
  • 8. Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China. [email protected].
  • 9. Institute of Chronic Nephropathy, Wenzhou Medical University, Wenzhou, 325035, China. [email protected].
  • # 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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