Journal article
Channel Function of Polycystin-2 in the Endoplasmic Reticulum Protects against Autosomal Dominant Polycystic Kidney Disease
Journal of the American Society of Nephrology, Vol.33(8), pp.1501-1516
08/01/2022
DOI: 10.1681/ASN.2022010053
PMCID: PMC9342640
PMID: 35835458
Abstract
BACKGROUNDMutations 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. METHODSThe 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. RESULTSAgonist-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. CONCLUSIONSPolycystin-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.
Details
- Title: Subtitle
- Channel Function of Polycystin-2 in the Endoplasmic Reticulum Protects against Autosomal Dominant Polycystic Kidney Disease
- Creators
- Biswajit PadhyJian XieRunping WangFang LinChou-Long Huang
- Resource Type
- Journal article
- Publication Details
- Journal of the American Society of Nephrology, Vol.33(8), pp.1501-1516
- DOI
- 10.1681/ASN.2022010053
- PMID
- 35835458
- PMCID
- PMC9342640
- NLM abbreviation
- J Am Soc Nephrol
- eISSN
- 1533-3450
- Grant note
- DOI: 10.13039/100000062, name: National Institute of Diabetes and Digestive and Kidney Diseases, award: DK109887, DK123610, P30DK090868
- Language
- English
- Date published
- 08/01/2022
- Academic Unit
- Anatomy and Cell Biology; Craniofacial Anomalies Research Center; Nephrology; Internal Medicine
- Record Identifier
- 9984297002502771
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