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Introduction <p>Epithelial-mesenchymal transition (EMT) plays a crucial role in diabetic kidney disease (DKD), particularly in the context of podocyte EMT. However, the regulatory networks controlling EMT activation in podocytes remain incompletely mapped. The FOS proto-oncogene (FOS) has emerged as a key player in EMT, yet its functional significance in DKD-podocytes remains poorly defined.</p> Methods <p>The predictive validity of FOS was confirmed through least absolute shrinkage and selection operator (LASSO) regression and multivariable logistic analysis in clinical data. A streptozotocin-induced DKD rat model was established, and podocyte cells (MPC5, HPC) treated with high glucose served as an in vitro model. The functional effect of FOS was explored using genetic interventions in vivo and in vitro.</p> Results <p>FOS expression is increased in patients with DKD, correlating with deterioration in renal function. LASSO and logistic analyses identified FOS as a robust predictor of DKD progression. FOS deficiency in vivo attenuated renal dysfunction and fibrosis. In podocytes, high glucose-primed FOS induced EMT and collagen accumulation, effects reversed by FOS knockdown. Crucially, FOS directly bound and activated Smad3, while Smad3 silencing abolished FOS-mediated injury.</p> Conclusion <p>This study demonstrates that the FOS/Smad3 axis is a critical contributor to coordinating EMT and fibrosis in diabetic renal podocytes, proposing a novel therapeutic target in DKD.</p>

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FOS drives podocyte injury and renal fibrosis in diabetic kidney disease via direct Smad3 binding

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月28日

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  • Man Sun,
  • Tianchi Yan,
  • Wenjing Zhao,
  • Zhifeng Cheng

摘要

Introduction

Epithelial-mesenchymal transition (EMT) plays a crucial role in diabetic kidney disease (DKD), particularly in the context of podocyte EMT. However, the regulatory networks controlling EMT activation in podocytes remain incompletely mapped. The FOS proto-oncogene (FOS) has emerged as a key player in EMT, yet its functional significance in DKD-podocytes remains poorly defined.

Methods

The predictive validity of FOS was confirmed through least absolute shrinkage and selection operator (LASSO) regression and multivariable logistic analysis in clinical data. A streptozotocin-induced DKD rat model was established, and podocyte cells (MPC5, HPC) treated with high glucose served as an in vitro model. The functional effect of FOS was explored using genetic interventions in vivo and in vitro.

Results

FOS expression is increased in patients with DKD, correlating with deterioration in renal function. LASSO and logistic analyses identified FOS as a robust predictor of DKD progression. FOS deficiency in vivo attenuated renal dysfunction and fibrosis. In podocytes, high glucose-primed FOS induced EMT and collagen accumulation, effects reversed by FOS knockdown. Crucially, FOS directly bound and activated Smad3, while Smad3 silencing abolished FOS-mediated injury.

Conclusion

This study demonstrates that the FOS/Smad3 axis is a critical contributor to coordinating EMT and fibrosis in diabetic renal podocytes, proposing a novel therapeutic target in DKD.