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Background <p>Alport syndrome (AS) is a hereditary kidney disease characterized by hematuria, proteinuria, and progressive kidney failure. Podocyte injury is an important feature of AS, but the underlying molecular mechanisms remain incompletely understood. Secreted protein acidic and rich in cysteine (SPARC) has been implicated in kidney injury and fibrosis; however, its role in AS-associated podocyte injury is unclear.</p> Methods <p>We examined SPARC expression and localization in kidneys from <i>Col4a3</i><sup><i>−/−</i></sup> AS mice and analyzed SPARC expression in urine and kidney samples from patients with AS. Mouse podocyte clone-5 cells (MPC5) with SPARC overexpression, with or without <i>Adgrb1</i> knockdown, were used to investigate injury-related changes in podocytes. RNA-seq was performed to explore candidate downstream signaling pathways.</p> Results <p>SPARC expression was increased in kidneys from <i>Col4a3</i><sup><i>−/−</i></sup> AS mice and was enriched in podocyte-associated regions. In pediatric patients with AS, urinary SPARC levels were elevated, and immunostaining for SPARC was observed in both glomerular and tubular compartments of kidney biopsy sections. In MPC5, <i>Sparc</i>-overexpression induced inflammatory cytokine expression, cytoskeletal disorganization, and increased permeability of the podocyte monolayer. Transcriptomic analysis identified <i>Adgrb1</i> as a markedly upregulated gene in <i>Sparc</i>-overexpressing podocytes. <i>Adgrb1</i> knockdown partially attenuated SPARC induced inflammatory and injury related changes. RNA-seq analysis further suggested that PI3K/AKT signaling pathway may be involved downstream of ADGRB1 in podocytes.</p> Conclusion <p>These findings suggest that SPARC is associated with podocyte injury in AS and that ADGRB1 may participate in SPARC-related podocyte responses. Elevated urinary SPARC in patients with AS supports its potential as a candidate biomarker. However, the mechanism linking SPARC to ADGRB1 remains unclear and warrants further investigation.</p>

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SPARC upregulation mediates podocyte injury in Alport syndrome mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月3日

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  • Dongxuan Chi,
  • Hongyuan Chu,
  • Jing Nie,
  • Yanqin Zhang,
  • Fang Wang,
  • Jie Ding

摘要

Background

Alport syndrome (AS) is a hereditary kidney disease characterized by hematuria, proteinuria, and progressive kidney failure. Podocyte injury is an important feature of AS, but the underlying molecular mechanisms remain incompletely understood. Secreted protein acidic and rich in cysteine (SPARC) has been implicated in kidney injury and fibrosis; however, its role in AS-associated podocyte injury is unclear.

Methods

We examined SPARC expression and localization in kidneys from Col4a3−/− AS mice and analyzed SPARC expression in urine and kidney samples from patients with AS. Mouse podocyte clone-5 cells (MPC5) with SPARC overexpression, with or without Adgrb1 knockdown, were used to investigate injury-related changes in podocytes. RNA-seq was performed to explore candidate downstream signaling pathways.

Results

SPARC expression was increased in kidneys from Col4a3−/− AS mice and was enriched in podocyte-associated regions. In pediatric patients with AS, urinary SPARC levels were elevated, and immunostaining for SPARC was observed in both glomerular and tubular compartments of kidney biopsy sections. In MPC5, Sparc-overexpression induced inflammatory cytokine expression, cytoskeletal disorganization, and increased permeability of the podocyte monolayer. Transcriptomic analysis identified Adgrb1 as a markedly upregulated gene in Sparc-overexpressing podocytes. Adgrb1 knockdown partially attenuated SPARC induced inflammatory and injury related changes. RNA-seq analysis further suggested that PI3K/AKT signaling pathway may be involved downstream of ADGRB1 in podocytes.

Conclusion

These findings suggest that SPARC is associated with podocyte injury in AS and that ADGRB1 may participate in SPARC-related podocyte responses. Elevated urinary SPARC in patients with AS supports its potential as a candidate biomarker. However, the mechanism linking SPARC to ADGRB1 remains unclear and warrants further investigation.