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Channel Function of Polycystin-2 in the Endoplasmic Reticulum Protects against Autosomal Dominant Polycystic Kidney

Biswajit Padhy1, Jian Xie1, Runping Wang1

  • 1Division of Nephrology, Department of Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa.

Journal of the American Society of Nephrology : JASN
|July 14, 2022
PubMed
Abstract

Insights

Polycystin-2 in the endoplasmic reticulum, not cilia, is key for preventing polycystic kidney disease. Activating TRIC-B channels may offer a new therapy for ADPKD by regulating ER calcium release.

Area of Science:

  • Nephrology
  • Cell Biology
  • Molecular Biology

Background:

  • Autosomal dominant polycystic kidney disease (ADPKD) is primarily linked to mutations in PKD2, encoding polycystin-2.
  • The prevailing theory implicates polycystin-2's role in calcium ion influx in primary cilia in ADPKD pathogenesis.
  • However, polycystin-2 is mainly found in the endoplasmic reticulum (ER) and is more permeable to potassium than calcium ions.

Purpose of the Study:

  • To investigate the function of ER-localized polycystin-2 in ADPKD.
  • To explore the role of the ER-resident potassium channel TRIC-B in ADPKD pathogenesis.
  • To utilize TRIC-B as a tool to study ER polycystin-2 function.

Main Methods:

  • Examined ER calcium ion release in cells with and without polycystin-2 or TRIC-B.
  • Utilized cultured cells, zebrafish, and mouse models to assess polycystin-2 and TRIC-B function.
  • Investigated the effects of TRIC-B expression and polycystin-2 localization on ADPKD phenotypes.

Main Results:

  • Absence of polycystin-2 impaired ER calcium release, which was restored by TRIC-B; conversely, TRIC-B deficiency was rescued by polycystin-2.
  • ER-localized polycystin-2, independent of cilia, corrected ER calcium release defects.
  • TRIC-B expression ameliorated cystogenesis in Pkd2-deficient mice, while TRIC-B deletion exacerbated it.

Conclusions:

  • ER-localized polycystin-2 is crucial for preventing cyst formation in ADPKD.
  • Polycystin-2 likely functions as a potassium channel in the ER, facilitating calcium release.
  • TRIC-B activators represent a potential therapeutic strategy for ADPKD.
Keywords:
ADPKDendoplasmic reticulumion channelpolycystin

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