PUBLICATION
Channel Function of Polycystin-2 in the Endoplasmic Reticulum Protects against Autosomal Dominant Polycystic Kidney Disease
- Authors
- Padhy, B., Xie, J., Wang, R., Lin, F., Huang, C.L.
- ID
- ZDB-PUB-220715-14
- Date
- 2022
- Source
- Journal of the American Society of Nephrology : JASN 33(8): 1501-1516 (Journal)
- Registered Authors
- Lin, Fang
- Keywords
- ADPKD, endoplasmic reticulum, ion channel, polycystin
- MeSH Terms
-
- Animals
- Calcium/metabolism
- Endoplasmic Reticulum/metabolism
- Inositol/metabolism
- Ion Channels/genetics
- Mice
- Polycystic Kidney, Autosomal Dominant*/genetics
- Polycystic Kidney, Autosomal Dominant*/metabolism
- Polycystic Kidney, Autosomal Dominant*/prevention & control
- Potassium/metabolism
- Potassium Channels
- TRPP Cation Channels*/genetics
- TRPP Cation Channels*/metabolism
- Zebrafish/metabolism
- PubMed
- 35835458 Full text @ J. Am. Soc. Nephrol.
Citation
Padhy, B., Xie, J., Wang, R., Lin, F., Huang, C.L. (2022) Channel Function of Polycystin-2 in the Endoplasmic Reticulum Protects against Autosomal Dominant Polycystic Kidney Disease. Journal of the American Society of Nephrology : JASN. 33(8):1501-1516.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping