Program in Molecular Medicine
First Thesis Advisor
Autosomal Dominant Polycystic Kidney Disease, JNK Mitogen-Activated Protein Kinases
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 polycystin 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 stress-activated mitogen-activated protein kinase (MAPK) pathway c-Jun N-terminal kinase (JNK) promotes proliferation in specific contexts and is activated in acute and chronic kidney disease. Previous work found evidence of JNK activation in cystic tissues (Le et al., 2005) and others showed that JNK signaling is activated by aberrant expression of PKD1 and PKD2 in cell culture (Arnould et al., 1998; Arnould et al., 1999; Parnell et al., 2002; Yu et al., 2010) but the contribution of JNK signaling to cystic disease in vivo has not been investigated.
This body of work describes the use of conditional and germline deletion of Pkd2, Jnk1 and Jnk2 to model ADPKD and JNK signaling inhibition in juvenile and adult mice. Immunoblots and histological staining were used to measure JNK activation and evaluate the effect of JNK deletion on cystic disease. Results show that Pkd2 deletion activated JNK signaling in juvenile and adult mice. Reduction of JNK activity significantly reduced cystic burden in kidneys of juvenile Pkd2 mutant mice. This correlated with reduced tubule cell proliferation and reduced kidney fibrosis. The improvement in cystic phenotype was driven primarily by Jnk1 deletion rather than Jnk2. JNK signaling inhibition in adult Pkd2 mutants significantly reduced liver cysts when mice were aged six months. JNK inhibition reduces the severity of cystic disease caused by the loss of Pkd2 suggesting that the JNK pathway should be explored as a potential therapeutic target for ADPKD.
Smith AO. (2021). Defining the Role of c-Jun N-terminal Kinase (JNK) Signaling in Autosomal Dominant Polycystic Kidney Disease. GSBS Dissertations and Theses. https://doi.org/10.13028/npkr-rh43. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/1141
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