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Dock5 Deficiency Promotes Proteinuric Kidney Diseases via Modulating Podocyte Lipid Metabolism

Hua Qu1, Xiufei Liu1, Jiaran Zhu1

  • 1Department of Endocrinology, Translational Research of Diabetes Key Laboratory of Chongqing Education Commission of China, the Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|December 31, 2023
PubMed

Insights

Dedicator of cytokinesis 5 (Dock5) deficiency worsens kidney disease by increasing podocyte lipid accumulation. Restoring Dock5 protects against podocyte injury and kidney disease progression.

Area of Science:

  • Nephrology
  • Cell Biology
  • Molecular Biology

Background:

  • Lipid accumulation in podocytes is a key factor in proteinuric kidney diseases.
  • The precise mechanisms driving podocyte lipotoxicity remain incompletely understood.

Purpose of the Study:

  • To investigate the role of dedicator of cytokinesis 5 (Dock5) in podocyte lipotoxicity and proteinuric kidney diseases.
  • To elucidate the molecular pathways linking Dock5 to lipid metabolism in podocytes.

Main Methods:

  • Screening for genes critical to podocyte lipotoxicity, focusing on Dock5.
  • Utilizing mouse models and patient samples of proteinuric kidney diseases.
  • Investigating the liver X receptor α (LXRα)/scavenger receptor class B (CD36) signaling pathway and m6A modification.

Main Results:

  • Dock5 expression is reduced in proteinuric kidney diseases.
  • Podocyte-specific Dock5 deficiency exacerbates kidney injury and glomeruli pathology.
  • Dock5 deficiency enhances CD36-mediated fatty acid uptake via upregulation of LXRα in an m6A-dependent manner.
  • Restoring Dock5 expression ameliorates podocyte injury and disease progression.

Conclusions:

  • Dock5 deficiency is a critical driver of podocyte lipotoxicity in proteinuric kidney diseases.
  • Dock5 modulates podocyte lipid metabolism through the LXRα/CD36 pathway.
  • Dock5 represents a potential therapeutic target for proteinuric kidney diseases.
Keywords:
Dock5lipid metabolismpodocytesproteinuric kidney diseases

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