UC Santa Barbara

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder associated with severe morbidity which affects over 500,000 individuals in the U.S. alone. In most cases ADPKD is caused by a loss-of-function mutation in the PKD1 gene that encodes polycystin-1 (PC1). While PC1 has been ascribed to regulating numerous signaling pathways that are dysregulated in ADPKD, much of these underlying mechanisms remain to be elucidated.

PC1 has been reported to interact with atypical protein kinase C (aPKC) which is a serine/threonine protein kinase. Data from our lab demonstrates that the zeta isozyme of aPKC (PKCζ) specifically binds to and phosphorylates the C-terminal tail of PC1. PKCζ also regulates functions which are known to be perturbed in ADPKD such as epithelial cell polarity, ciliogenesis, calcium signaling and metabolism. We thus sought to investigate whether PKCζ activity is altered in PKD.

We report here that PKCζ expression is aberrantly downregulated in ADPKD patients as well as in two PKD mouse models. We demonstrate that pharmacologically activating PKCζ using the FDA approved drug FTY720 ameliorates various markers of disease progression in multiple mouse models. Furthermore, treatment of PKCζ knockout mice with the drug revealed reduced efficacy, suggesting a PKCζ specific mechanism of action. Our data proposes PKCζ deficiency as a possible driver of PKD and assesses its potential as a drug target in the treatment of ADPKD.

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