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Background <p>Cardiotrophin-like cytokine factor 1 (CLCF1) is shown to enhance glomerular albumin permeability, contributing to proteinuria. However, its specific involvement in diabetic kidney disease (DKD) remains undefined. This study aimed&#xa0;to explore the mechanistic contribution of CLCF1 to endothelial-to-mesenchymal transition (EndMT) in DKD.</p> Methods <p>CLCF1 expression in patients with DKD and high glucose (HG)-stimulated human glomerular endothelial cells (HRGECs) was quantified via quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemistry (IHC). The effects of CLCF1 on HG-induced EndMT and the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling cascade were assessed through qRT-PCR and Western blot analysis. Additionally, the role of JAK2/STAT3 activation in mediating EndMT was examined using the JAK2/STAT3 agonist colivelin in CLCF1-knockdown HRGECs.</p> Results <p>In patients with DKD and HG-stimulated HRGECs, CLCF1 mRNA and protein expression were elevated (<i>p</i> &lt; 0.001 and <i>p</i> &lt; 0.001 for mRNA; <i>p</i> &lt; 0.001 and <i>p</i> &lt; 0.001 for protein). CLCF1 knock- down attenuated HG-induced EndMT, as evidenced by reduced α-Smooth Muscle Actin(α-SMA) and vimentin expression (qRT-PCR/Western blot: α-SMA: <i>p</i> &lt; 0.001 for both; vimentin <i>p</i> &lt; 0.001/ <i>p</i> = 0.004). Conversely, CLCF1 overexpression promoted EndMT and activated the JAK2/STAT3 pathway, with concordant qPCR (α-SMA: <i>p</i> &lt; 0.001 for both; vimentin: <i>p</i> &lt; 0.001 for both) and Western blot (α-SMA: <i>p</i> &lt; 0.001; vimentin: <i>p</i> &lt; 0.001; p-JAK2: <i>p</i> = 0.010; p-STAT3: <i>p</i> = 0.005). Notably, the protective effect of CLCF1 knockdown was abolished by colivelin.</p> Conclusion <p>These findings demonstrate that CLCF1 mediates HG-induced EndMT in HRGECs via modulation of the JAK2/STAT3 pathway. This indicates that the CLCF1/JAK2/STAT3 signaling axis plays a role in the pathogenesis of DKD.</p>

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CLCF1 contributes to high-glucose-induced EndMT by modulating JAK2/STAT3 signaling

  • 期刊论文

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  • 发表日期：

    2025年7月29日

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  • Rongrong Deng,
  • Kaiying He,
  • Qicai You,
  • Wenkai Zhang,
  • Xuezhen Ma,
  • Xiaochun Zhou,
  • Yuke Kong,
  • Jianqin Wang

摘要

Background

Cardiotrophin-like cytokine factor 1 (CLCF1) is shown to enhance glomerular albumin permeability, contributing to proteinuria. However, its specific involvement in diabetic kidney disease (DKD) remains undefined. This study aimed to explore the mechanistic contribution of CLCF1 to endothelial-to-mesenchymal transition (EndMT) in DKD.

Methods

CLCF1 expression in patients with DKD and high glucose (HG)-stimulated human glomerular endothelial cells (HRGECs) was quantified via quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemistry (IHC). The effects of CLCF1 on HG-induced EndMT and the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling cascade were assessed through qRT-PCR and Western blot analysis. Additionally, the role of JAK2/STAT3 activation in mediating EndMT was examined using the JAK2/STAT3 agonist colivelin in CLCF1-knockdown HRGECs.

Results

In patients with DKD and HG-stimulated HRGECs, CLCF1 mRNA and protein expression were elevated (p < 0.001 and p < 0.001 for mRNA; p < 0.001 and p < 0.001 for protein). CLCF1 knock- down attenuated HG-induced EndMT, as evidenced by reduced α-Smooth Muscle Actin(α-SMA) and vimentin expression (qRT-PCR/Western blot: α-SMA: p < 0.001 for both; vimentin p < 0.001/ p = 0.004). Conversely, CLCF1 overexpression promoted EndMT and activated the JAK2/STAT3 pathway, with concordant qPCR (α-SMA: p < 0.001 for both; vimentin: p < 0.001 for both) and Western blot (α-SMA: p < 0.001; vimentin: p < 0.001; p-JAK2: p = 0.010; p-STAT3: p = 0.005). Notably, the protective effect of CLCF1 knockdown was abolished by colivelin.

Conclusion

These findings demonstrate that CLCF1 mediates HG-induced EndMT in HRGECs via modulation of the JAK2/STAT3 pathway. This indicates that the CLCF1/JAK2/STAT3 signaling axis plays a role in the pathogenesis of DKD.