2. Academic Validation
  3. ERK1/2-dependent activity of SOX9 is required for sublytic C5b-9-induced expression of FGF1, PDGFα, and TGF-β1 in rat Thy-1 nephritis

ERK1/2-dependent activity of SOX9 is required for sublytic C5b-9-induced expression of FGF1, PDGFα, and TGF-β1 in rat Thy-1 nephritis

  • Int Immunopharmacol. 2023 Dec 19:127:111372. doi: 10.1016/j.intimp.2023.111372.
Zhijiao Wu 1,  Zhiwei Zhang 1,  Sicheng Zhou 2,  Mengxiao Xie 1,  Longfei Liu 1,  Can Luo 1,  Feixiang Zheng 3,  Wen Qiu 4,  Yingwei Wang 4,  Jing Zhang 5
Affiliations

Affiliations

  • 1 Department of Immunology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
  • 2 School of Pediatrics, Nanjing Medical University, Nanjing, China.
  • 3 School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
  • 4 Department of Immunology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China; Key Laboratory of Immune Microenvironment and Disease, Nanjing Medical University, Nanjing, China; National Health Commission Key Laboratory of Antibody Techniques, Nanjing Medical University, Nanjing, China.
  • 5 Department of Immunology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China; Key Laboratory of Immune Microenvironment and Disease, Nanjing Medical University, Nanjing, China; National Health Commission Key Laboratory of Antibody Techniques, Nanjing Medical University, Nanjing, China. Electronic address: [email protected].
PMID: 38118314 DOI: 10.1016/j.intimp.2023.111372
Abstract

Mesangial proliferative glomerulonephritis (MsPGN) and its related rat model Thy-1 nephritis (Thy-1N) are associated with C5b-9 deposition and are characterized by proliferation of glomerular mesangial cell (GMC) and expansion of extracellular matrix (ECM) expansion, alongside overexpression of multiple growth factors. Although Fibroblast Growth Factor 1 (FGF1), platelet-derived growth factor alpha (PDGFα), and transforming growth factor beta 1 (TGF-β1) are well known for their proproliferative and profibrotic roles, the molecular mechanisms responsible for regulating the expression of these growth factors have not been thoroughly elucidated. In this study, we found that sublytic C5b-9 induction of sex-determining region Y-box 9 (SOX9) transactivated FGF1, PDGFα, and TGF-β1 genes in GMCs, resulting in a significant increase in their mRNA and protein levels. Besides, sublytic C5b-9 induction of activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylated SOX9 at serine 181 and serine 64, which enhanced SOX9's ability to transactivate FGF1, PDGFα, and TGF-β1 genes in GMCs. Furthermore, we demonstrated that inhibiting ERK1/2 activation or silencing either ERK1/2 or SOX9 gene led to reduced SOX9 phosphorylation, decreased generation of FGF1, PDGFα, and TGF-β1, and ameliorated glomerular injury in rat Thy-1N. Overall, these findings suggest that expression of FGF1, PDGFα, and TGF-β1 is promoted by ERK1/2-mediated phosphorylation of SOX9, which may provide a valuable insight into the pathogenesis of MsPGN and offer a potential target for the development of novel treatment strategies for MsPGN.

Keywords

Growth factor; Mesangial proliferative glomerulonephritis; Phosphorylation; SOX9; Sublytic C5b-9.

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