期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：30
DOI：10.1073/pnas.2121267119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder commonly caused by mutations in polycystin-1. The disease is associated with severe morbidity and has limited therapeutic options, with most patients requiring dialysis or transplantation by the sixth decade. Our work adds to understanding polycystic kidney disease (PKD) pathogenesis by clarifying the role of PKCζ in ADPKD and by presenting PKCζ as a potential therapeutic target. We show that PKCζ phosphorylates polycystin-1 at two specific serine residues. We demonstrate that PKCζ is aberrantly down-regulated in human ADPKD and mouse models of PKD and that its activity can be restored via treatment with the US Food and Drug Administration–approved drug FTY720. Last, we demonstrate that FTY720 treatment ameliorates disease progression in PKD mouse models and that these improvements are dependent on PKCζ expression.
Autosomal dominant polycystic kidney disease (ADPKD) affects more than 500,000 individuals in the United States alone. In most cases, ADPKD is caused by a loss-of-function mutation in the
PKD1 gene, which encodes polycystin-1 (PC1). Previous studies reported that PC1 interacts with atypical protein kinase C (aPKC). Here we show that PC1 binds to the ζ isoform of aPKC (PKCζ) and identify two PKCζ phosphorylation sites on PC1’s C-terminal tail. PKCζ expression is down-regulated in patients with ADPKD and orthologous and nonorthologous PKD mouse models. We find that the US Food and Drug Administration–approved drug FTY720 restores PKCζ expression in in vitro and in vivo models of polycystic kidney disease (PKD) and this correlates with ameliorated disease progression in multiple PKD mouse models. Importantly, we show that FTY720 treatment is less effective in PKCζ null versions of these PKD mouse models, elucidating a PKCζ-specific mechanism of action that includes inhibiting STAT3 activity and cyst-lining cell proliferation. Taken together, our results reveal that PKCζ down-regulation is a hallmark of PKD and that its stabilization by FTY720 may represent a therapeutic approach to the treat the disease.
关键词：enpolycystic kidney diseasepolycystin-1protein kinase C ζ
