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

Abstract

BACKGROUND:

Mutations of PKD2, which encodes polycystin-2, cause autosomal dominant polycystic kidney disease (ADPKD). The prevailing view is that defects in polycystin-2-mediated calcium ion influx in the primary cilia play a central role in the pathogenesis of cyst growth. However, polycystin-2 is predominantly expressed in the endoplasmic reticulum (ER) and more permeable to potassium ions than to calcium ions.

METHODS:

The trimeric intracellular cation (TRIC) channel TRIC-B is an ER-resident potassium channel that mediates potassium-calcium counterion exchange for inositol trisphosphate-mediated calcium ion release. Using TRIC-B as a tool, we examined the function of ER-localized polycystin-2 and its role in ADPKD pathogenesis in cultured cells, zebrafish, and mouse models.

RESULTS:

Agonist-induced ER calcium ion release was defective in cells lacking polycystin-2 and reversed by exogenous expression of TRIC-B. Vice versa, exogenous polycystin-2 reversed an ER calcium-release defect in cells lacking TRIC-B. In a zebrafish model, expression of wild-type but not nonfunctional TRIC-B suppressed polycystin-2-deficient phenotypes. Similarly, these phenotypes were suppressed by targeting the ROMK potassium channel (normally expressed on the cell surface) to the ER. In cultured cells and polycystin-2-deficient zebrafish phenotypes, polycystin-2 remained capable of reversing the ER calcium release defect even when it was not present in the cilia. Transgenic expression of Tric-b ameliorated cystogenesis in the kidneys of conditional Pkd2-inactivated mice, whereas Tric-b deletion enhanced cystogenesis in Pkd2-heterozygous kidneys.

CONCLUSIONS:

Polycystin-2 in the ER appears to be critical for anticystogenesis and likely functions as a potassium ion channel to facilitate potassium-calcium counterion exchange for inositol trisphosphate-mediated calcium release. The results advance the understanding of ADPKD pathogenesis and provides proof of principle for pharmacotherapy by TRIC-B activators.

• Authors: Biswajit Padhy, Jian Xie, Runping Wang, Fang Lin, Chou-Long Huang
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 33 Issue 8 Pg. 1501-1516 (08 2022) ISSN: 1533-3450 [Electronic] United States
• PMID: 35835458 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2022 by the American Society of Nephrology.

Chemical References

• Ion Channels
• Potassium Channels
• TRIC-B protein, mouse
• TRPP Cation Channels
• Inositol
• Potassium
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Endoplasmic Reticulum (metabolism)
• Inositol (metabolism)
• Ion Channels (genetics)
• Mice
• Polycystic Kidney, Autosomal Dominant (genetics, metabolism, prevention & control)
• Potassium (metabolism)
• Potassium Channels
• TRPP Cation Channels (genetics, metabolism)
• Zebrafish (metabolism)