Smith, Abigail OJonassen, Julie A.Preval, Kenley MDavis, Roger J.Pazour, Gregory J.2022-08-232022-08-232021-07-152021-08-26<p>bioRxiv 2021.07.15.452451; doi: https://doi.org/10.1101/2021.07.15.452451. <a href="https://doi.org/10.1101/2021.07.15.452451" target="_blank" title="view preprint in bioRxiv">Link to preprint on bioRxiv.</a></p>10.1101/2021.07.15.452451https://hdl.handle.net/20.500.14038/29871<p>This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.</p>Polycystic 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.en-USThe copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.http://creativecommons.org/licenses/by/4.0/Geneticsautosomal dominant polycystic kidney diseasemutationsc-Jun N-terminal kinase (JNK) pathwayAmino Acids, Peptides, and ProteinsCell BiologyCellular and Molecular PhysiologyCongenital, Hereditary, and Neonatal Diseases and AbnormalitiesEnzymes and CoenzymesFemale Urogenital Diseases and Pregnancy ComplicationsGenetics and GenomicsMale Urogenital DiseasesPreprinthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=3097&amp;context=faculty_pubs&amp;unstamped=1https://escholarship.umassmed.edu/faculty_pubs/207824506520faculty_pubs/2078