内质网
纤毛
细胞生物学
常染色体显性多囊肾病
生物学中的钙
钙
内分泌学
生物
多囊肾病
内科学
钙信号传导
钾通道
化学
细胞内
肾
医学
作者
Biswajit Padhy,Jian Xie,Runping Wang,Fang Lin,Chou Long Huang
出处
期刊:Journal of the American Society of Nephrology
[American Society of Nephrology]
日期:2022-07-14
卷期号:33 (8): 1501-1516
被引量:2
标识
DOI:10.1681/asn.2022010053
摘要
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.
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