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Single Gene Mutations in Pkd1 or Tsc2 Alter Extracellular Vesicle Production and Trafficking

Prashant Kumar1,2,3, Fahad Zadjali1,2,4, Ying Yao1,2

  • 1Department of Pediatrics, Le Bonheur Children's Hospital, University of Tennessee Health Science Center, Memphis, TN 38103, USA.

Biology
|May 28, 2022
PubMed

Insights

Extracellular vesicles (EVs) play a role in polycystic kidney disease (PKD). Loss of specific genes increases EV production and uptake, promoting disease progression in kidney cells.

Area of Science:

  • Nephrology
  • Cell Biology
  • Molecular Biology

Background:

  • Autosomal dominant polycystic kidney disease (ADPKD) and tuberous sclerosis complex (TSC) are genetic kidney diseases characterized by cyst formation and kidney dysfunction.
  • Extracellular vesicles (EVs) are implicated in mediating these renal cystic diseases by influencing genetically normal cells.

Purpose of the Study:

  • To investigate the role of extracellular vesicles (EVs) in the pathogenesis of polycystic kidney disease (PKD).
  • To examine how the loss of Tsc2 and Pkd1 genes affects EV production, characteristics, and cellular uptake.

Main Methods:

  • EVs were isolated using centrifugation and size exclusion chromatography.
  • EV characterization involved tunable resistive pulse sensing, dynamic light scattering, transmission electron microscopy, and Western blot analysis.
  • EV trafficking and uptake were studied in cell culture and in vivo using dye-based approaches.

Main Results:

  • Loss of the Tsc2 or Pkd1 gene significantly increased EV production.
  • EVs derived from cells lacking Tsc2 or Pkd1 showed enhanced uptake by renal epithelial cells and a prolonged half-life.
  • Disruption of primary cilia reduced EV production in renal collecting duct cells.
  • Pkd1 gene disruption in EVs altered their kinetics and prolonged their half-life.

Conclusions:

  • EVs play a significant role in the pathogenesis of polycystic kidney disease.
  • Primary cilia and EVs exhibit an interplay in renal cystic disease development.
  • EVs from cells with disrupted Pkd1 may have a prolonged effect on recipient cells, contributing to disease progression.

Keywords:
autosomal dominant polycystic kidney disease (ADPKD)cystogenesisextracellular vesicles (EVs)primary ciliarenal cysttuberous sclerosis complex (TSC)

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