Restoration of atypical protein kinase C ζ function in autosomal dominant polycystic kidney disease ameliorates disease progression.

Abstract

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.

• Authors: Masaw Akbari, Jonathan D West, Nicholas Doerr, Kevin R Kipp, Neda Marhamati, Sabrina Vuong, Yidi Wang, Markus M Rinschen, Jeffrey J Talbot, Oliver Wessely, Thomas Weimbs
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 119 Issue 30 Pg. e2121267119 (07 26 2022) ISSN: 1091-6490 [Electronic] United States
• PMID: 35867829 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural)

Chemical References

• TRPP Cation Channels
• protein kinase C zeta
• Protein Kinase C
• Fingolimod Hydrochloride

Topics

• Animals
• Disease Models, Animal
• Disease Progression
• Enzyme Activation
• Fingolimod Hydrochloride (pharmacology, therapeutic use)
• Humans
• Mice
• Polycystic Kidney, Autosomal Dominant (drug therapy, enzymology)
• Protein Kinase C (metabolism)
• TRPP Cation Channels (genetics, metabolism)