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

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.

Metabolism-based approaches for autosomal dominant polycystic kidney disease

“…Increased cAMP due to vasopressin ( Chebib et al, 2015 ) but likely also to decreased phosphodiesterases (PDEs) ( Pinto et al, 2016 ) play a key role in generating fluid-filled cysts. Defects in PC1 and PC2 mediated calcium ion influx in the primary cilia and/or in the endoplasmic reticulum (ER) ( Nauli et al, 2003 ; Padhy et al, 2022 ). Decreased intracellular calcium seems to convert the antiproliferative to proliferative effect of cAMP ( Yamaguchi et al, 2003 ) causing activation of MEK-ERK and increased cell proliferation.…”

Polycystin-2 in the Endoplasmic Reticulum: Bending Ideas about the Role of the Cilium

“…Although the data that Polycystins participate in ciliary mechanosensation are quite strong, there is less direct experimental proof for the widely held belief that it is this involvement in ciliary mechanosensation that constitutes the primary physiologic role of Polycystin-2, the loss of which leads to the development of cystic disease. The exciting and surprising results reported in this issue of he Journal of the American Society of Nephrology by Padhy et al 5 strongly suggest the time has come for this presumption to emulate the cilium, and thus to bend.…”

Regulation of PKD2 channel by TACAN: how does it link to cystogenesis in autosomal dominant polycystic kidney disease?

“…Since most PKD2 is ubiquitously expressed in the ER of different cells and organs, the ER‐localized PKD2 may have some physiological significance. Furthermore, the latest evidence showed that the functional PKD2 channel in the ER is protective in ADPKD mouse models, highlighting the importance of ER‐localized PKD2 during cystogenesis (Padhy et al., 2022). Therefore, future studies could explore the implications of TACAN on the function of PKD2 in different subcellular localizations.…”