c-JUN n-Terminal Kinase (JNK) Signaling in Autosomal Dominant 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 and is caused by mutations in the transmembrane proteins polycystin-1 (Pkd1) and polycystin-2 (Pkd2). The mechanisms by which polycystin mutations induce cyst formation are not well understood, however pro-proliferative signaling must be involved for tubule epithelial cell number to increase over time. We recently found that the stress-activated mitogen-activated protein kinase (MAPK) pathway c-Jun N-terminal kinase (JNK) pathway is activated in cystic disease and genetically removing JNK reduces cyst growth driven by a loss of Pkd2. This review covers the current state of knowledge of signaling in ADPKD with an emphasis on the JNK pathway.

Keywords: Cilia; Jun N Terminal kinase; Mitogen-activated protein kinase signaling; Mus musculus; Polycystic kidney disease; Polycystin-1; Polycystin-2.

Figure 1:. Cyst initiation in ADPKD requires a secondary insult.

Although ADPKD is dominantly inherited, cyst initiation is recessive at the cellular level. Cyst initiation occurs when tubule epithelial cells harboring one mutated allele of Pkd1 or Pkd2 receive a secondary insult, either by spontaneous somatic mutation of the healthy allele (two-hit hypothesis) or by any mechanism that reduces the function of the polycystin proteins below a critical threshold (threshold model). Created with BioRender.com

Figure 2:. Threshold model of cyst initiation incorporates cystic disease caused by polycystin overexpression.

Mice completely lacking Pkd1 or Pkd2 from conception demonstrate the most severe disease (embryonic lethality). Conditional homozygous deletion either postnatally or with tissue-specificity also induces severe disease with early mortality. Heterozygous mutants exhibit milder disease, suggesting that the closer to the wild-type range of gene expression, the milder the disease phenotype. Interestingly, expressing higher than normal levels of the polycystins has also been shown to cause cystic disease. The figure depicts a “threshold model” or dose-dependent model for developing cystic disease. Created with BioRender.com

Figure 3:. Disrupted calcium and cAMP signaling promotes cystic changes in tubule epithelial cells.

Mutations in Pkd1 and Pkd2 in tubule epithelial cells result in lowered intracellular calcium, increased cAMP production, and altered sensitivity to cAMP. High intracellular cAMP levels promote fluid secretion via CFTR channels and increased proliferation via PKA/MEK/ERK. Fluid secretion and proliferation promote kidney cyst formation and expansion. Created with BioRender.com

Figure 4:. JNK is a stress-activated MAP kinase phosphorylation cascade.

A variety of upstream stressors activate JNK through a phosphorylation cascade including MAP3Ks, MAP2Ks and JNKs. JNK1 and JNK2 are expressed ubiquitously including in the kidney and liver epithelium. Phosphorylated JNKs activate downstream targets such as AP-1 transcription factor subunits to control diverse cellular processes including proliferation, differentiation and cell survival. Created with BioRender.com