c-Jun N-terminal kinase (JNK) signaling contributes to cystic burden in polycystic kidney disease
Student AuthorsAbigail O. Smith
Kenley M. Preval
UMass Chan AffiliationsMicrobiology and Physiological Systems
Morningside Graduate School of Biomedical Sciences
Program in Molecular Medicine
Document TypeJournal Article
c-Jun N-terminal kinase signaling cascade
Polycystic kidney disease
MetadataShow full item record
AbstractPolycystic kidney disease is an inherited degenerative disease in which the uriniferous tubules are replaced by expanding fluid-filled cysts that ultimately destroy organ function. Autosomal dominant polycystic kidney disease (ADPKD) is the most common form, afflicting approximately 1 in 1,000 people. It primarily is caused by mutations in the transmembrane proteins polycystin-1 (Pkd1) and polycystin-2 (Pkd2). The most proximal effects of Pkd mutations leading to cyst formation are not known, but pro-proliferative signaling must be involved for the tubule epithelial cells to increase in number over time. The c-Jun N-terminal kinase (JNK) pathway promotes proliferation and is activated in acute and chronic kidney diseases. Using a mouse model of cystic kidney disease caused by Pkd2 loss, we observe JNK activation in cystic kidneys and observe increased nuclear phospho c-Jun in cystic epithelium. Genetic removal of Jnk1 and Jnk2 suppresses the nuclear accumulation of phospho c-Jun, reduces proliferation and reduces the severity of cystic disease. While Jnk1 and Jnk2 are thought to have largely overlapping functions, we find that Jnk1 loss is nearly as effective as the double loss of Jnk1 and Jnk2. Jnk pathway inhibitors are in development for neurodegeneration, cancer, and fibrotic diseases. Our work suggests that the JNK pathway should be explored as a therapeutic target for ADPKD.
SourceSmith AO, Jonassen JA, Preval KM, Davis RJ, Pazour GJ. c-Jun N-terminal kinase (JNK) signaling contributes to cystic burden in polycystic kidney disease. PLoS Genet. 2021 Dec 28;17(12):e1009711. doi: 10.1371/journal.pgen.1009711. PMID: 34962918; PMCID: PMC8746764.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/51990
Related ResourcesThis article is based on a previously available preprint in bioRxiv, https://doi.org/10.1101/2021.07.15.452451.
RightsCopyright: © 2021 Smith et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.; Attribution 4.0 International
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Except where otherwise noted, this item's license is described as Copyright: © 2021 Smith et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.; Attribution 4.0 International