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Aberrant Regulation of Notch3 Signaling Pathway in Polycystic Kidney Disease

Jessica Idowu1,2, Trisha Home1,2, Nisha Patel1,2

  • 1Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, United States.

Scientific Reports
|February 22, 2018
PubMed

Insights

Polycystic kidney disease (PKD) involves kidney and liver cysts. Targeting the Notch3 pathway, which drives cyst growth and cell proliferation, offers a potential therapeutic strategy for PKD.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Genetics

Background:

  • Polycystic kidney disease (PKD) is a genetic disorder causing kidney and liver cysts, leading to end-stage renal disease.
  • No globally approved therapies currently exist for PKD.
  • The Notch signaling pathway regulates cell proliferation and differentiation, processes implicated in PKD pathogenesis.

Purpose of the Study:

  • To investigate the role of the Notch signaling pathway in PKD.
  • To determine if Notch pathway activation contributes to cyst formation and epithelial cell proliferation in PKD.
  • To evaluate the therapeutic potential of Notch inhibition in PKD.

Main Methods:

  • Assessed Notch signaling component expression in mouse models (ARPKD, ADPKD) and human ADPKD patient kidneys.
  • Correlated Notch3 expression with cyst growth and cell proliferation marker (PCNA).
  • Inhibited Notch signaling in primary human ADPKD cells and assessed effects on proliferation and cystogenesis in vitro.

Main Results:

  • Notch pathway members, especially Notch3, were upregulated in cyst-lining epithelial cells of PKD models and patients.
  • Notch3 expression correlated with rapid cyst growth and cell proliferation.
  • Notch inhibition reduced Notch3 activation, cell proliferation, and cyst formation/growth in human ADPKD cells.

Conclusions:

  • Aberrant Notch3 activation promotes epithelial cell proliferation in PKD.
  • Inhibition of Notch signaling presents a promising therapeutic approach to prevent cyst formation and growth in PKD.

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