Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common form of PKD, with an estimated prevalence of 1:400 - 1:1,000 births, and is characterized by progressive renal cyst formation resulting in end stage kidney failure during the 5th-7th decade of life. Mutations in PKD1 or PKD2, genes encoding polycystin-1 (PC-1) and polycystin-2 (PC-2), are responsible for the development of ADPKD. The detailed mechanism of renal cyst initiation is still unknown, but a central hypothesis is that loss/reduction of functional PKD1 or PKD2 in cilia perturbs epithelial signaling biology resulting in cyst development. It is well established that the Wnt signaling pathway plays an important role in early kidney development, but is deactivated at later stages. Analysis of cyst linings from ADPKD patients and kidneys from Pkd1 null mice indicate that canonical Wnt signaling is upregulated. Given the need to uncover other specific pathways that may limit cystic expansion and renal function decline, it is important to determine if Wnt signaling is also upregulated in slowly developing Pkd1 mouse models and if modulation of Wnt can effect cyst development in vivo. To address this important question, our laboratory has generated and extensively characterized a model of slowly progressing ADPKD. I will use this model to address the following specific aims: (1) Characterize when and how Wnt signaling is dysregulated in ADPKD and the effect of Pkd1 dosage on Wnt signaling. To complete aim 1, I will (a) use a Wnt reporter mouse to quantify changes in Wnt activation in cyst linings of Pkd1RC mice, (b) analyze global transcriptome changes in cystic and non-cystic tubules to determine the impact on Wnt target genes, and (c) assay Wnt responsiveness in MEFs isolated from Pkd1 mice with altered PC-1 expression levels. (2) Determine whether modulation of the canonical Wnt signaling pathway can ameliorate cyst initiation, expansion, and maintenance in ADPKD. To complete aim 2, I will modulate Wnt signaling in the kidneys of Pkd1RC/RC mice and analyze changes in cyst development. The rationale for performing this research is to deepen our understanding of the mechanism of cyst progression, and to determine if this pathway should be considered for therapeutic intervention.
Autosomal Dominant Polycystic Kidney disease (ADPKD) is a common genetically inherited disease with an estimated prevalence of 1:400 - 1:1,000 births and is characterized by bilateral renal cyst formation ultimately resulting in end stage kidney during the 5th to 7th decade of life. Although many experimental therapeutics have been shown to slow cystogenesis in animal models, they are unable to significantly reverse cystic expansion and simultaneously improve renal function. Exploring other pathways that may be responsible for cyst expansion, such as the Wnt pathway could result in new efficacious therapies that can be used in combination with previous discovered therapies.
