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.
Highlights
Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of inherited kidney disease, afflicting approximately 1 in 1,000 people in the United States and worldwide
Pkd1 or Pkd2 loss leads to reduced intracellular calcium and, subsequently, an abnormal cellular response to cyclic adenosine monophosphate levels [5,6,7] In mutant epithelial cells, elevated cAMP promotes increased fluid secretion and epithelial cell proliferation [8] cAMP reduction via vasopressin 2 receptor antagonism is the mechanism of action of tolvaptan, the single FDA-approved drug for patients with ADPKD [9,10] tolvaptan slows but does not halt disease progression and is not appropriate for all ADPKD patients due to side effects
Prior studies showed that the c-Jun N-terminal kinase (JNK) signaling pathway is activated in cells overexpressing exogenous Pkd1 [12,13] or Pkd2 [14] constructs
Summary
Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of inherited kidney disease, afflicting approximately 1 in 1,000 people in the United States and worldwide. The majority of ADPKD cases are due to mutations in either of two transmembrane proteins, polycystin-1 (Pkd1) and polycystin-2 (Pkd2), that form a heterotetrameric complex in the primary ciliary membranes [1] It is widely believed that perturbing this ciliary complex, either by loss-of-function mutations or disrupting cilia structure triggers the cellular phenotype that leads to cyst formation [2,3,4] the precise mechanism by which the polycystin complex preserves tubule architecture remains obscure, some aspects of pro-cystic signaling have been established. Increased AP-1 levels have been detected in cystic kidneys in humans and mice [16] AP-1 promotes proliferation and cell survival by regulating oncogene transcription [19] including c-Myc, which was recently shown to contribute directly to cystic kidney disease [20,21]
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