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Updated: Jun 23, 2025

Implementing Patch Clamp and Live Fluorescence Microscopy to Monitor Functional Properties of Freshly Isolated PKD Epithelium
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Myocardin-Related Transcription Factor Mediates Epithelial Fibrogenesis in Polycystic Kidney Disease

Zsuzsanna Lichner1, Mei Ding1, Tarang Khare1,2

  • 1Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON M5B 1T8, Canada.

Cells
|June 19, 2024
PubMed

Insights

Polycystic kidney disease (PKD) involves cyst formation and fibrosis. Loss of Polycystin 1/2 activates the RhoA/cytoskeleton/myocardin-related transcription factor (MRTF) pathway, driving epithelial fibrosis in PKD.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Cell Biology

Background:

  • Polycystic kidney disease (PKD) is marked by cyst development and fibrosis.
  • The molecular pathways linking Polycystin 1/2 (PC1/2) dysfunction to fibrosis remain unclear.
  • The RhoA pathway is implicated in cystogenesis, suggesting a potential role in fibrosis.

Purpose of the Study:

  • To investigate the role of the myocardin-related transcription factor (MRTF) in PC1/2 loss-induced epithelial fibrogenesis in PKD.
  • To determine if MRTF activation is a consequence of PC1/2 loss and contributes to PKD pathogenesis.

Main Methods:

  • siRNA-mediated knockdown of PC1/2 in vitro.
  • Analysis of RhoA activation, cytoskeletal remodeling, and MRTF nuclear translocation/overexpression.
  • In vivo studies using PKD mouse models (PKD1 and PKD2).
  • Gene expression analysis to identify MRTF-dependent genes.

Main Results:

  • PC1/2 loss in vitro activated RhoA, induced cytoskeletal changes, and led to MRTF nuclear translocation and overexpression.
  • Similar MRTF activation was observed in epithelial cells of PKD mouse models.
  • A significant number of genes upregulated by PC1/2 downregulation were MRTF-dependent.
  • Epithelial MRTF was essential for fibroblast activation, promoting fibrosis.

Conclusions:

  • MRTF is a key mediator of epithelial fibrogenesis in PKD, activated downstream of PC1/2 loss.
  • The RhoA/cytoskeleton/MRTF pathway is a critical link between PC1/2 dysfunction and epithelial fibrosis.
  • RhoA may be a common upstream regulator of both cystogenesis and fibrosis in PKD.
Keywords:
epithelium-initiated fibrosismyocardin-related transcription factorprofibrotic epithelial phenotype∙ polycystic kidney disease

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