c-Jun N-terminal kinase (JNK) signaling contributes to cystic burden in polycystic kidney disease

Abstract

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.

Illumination of understudied ciliary kinases

“…Ciliopathies can be quite organ-specific with examples such as polycystic kidney disease, retinitis pigmentosa, and nephronophthisis. They can also be pleiotropic disorders, like cerebello-oculo-renal syndrome, Primary Ciliary Dyskinesia (PCD), Bardet-Biedl syndrome, Meckel-Gruber syndrome, orofaciodigital syndrome 1, Joubert syndrome, STAR syndrome, and Jeune asphyxiating thoracic dystrophy (Zaghloul and Katsanis, 2009;Hildebrandt et al, 2011;Lee and Gleeson, 2011;Wirschell et al, 2011;Guen et al, 2016;Goto et al, 2017;Smith et al, 2022;Benmerah et al, 2023). More comprehensive reviews of ciliopathies provide additional details on their inheritance, genetics, clinical symptoms, and other features (Hildebrandt et al, 2011;Lee and Gleeson, 2011;Christensen et al, 2012;Abraham et al, 2022;Modarage et al, 2022).…”