Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease

Abstract

Recent advances in defining the genetic mechanisms of disease causation and modification in autosomal dominant polycystic kidney disease (ADPKD) have helped to explain some extreme disease manifestations and other phenotypic variability. Studies of the ADPKD proteins, polycystin-1 and -2, and the development and characterization of animal models that better mimic the human disease, have also helped us to understand pathogenesis and facilitated treatment evaluation. In addition, an improved understanding of aberrant downstream pathways in ADPKD, such as proliferation/secretion-related signaling, energy metabolism, and activated macrophages, in which cAMP and calcium changes may play a role, is leading to the identification of therapeutic targets. Finally, results from recent and ongoing preclinical and clinical trials are greatly improving the prospects for available, effective ADPKD treatments.

Figure 1. An abnormal crosstalk of calcium and cAMP signaling disrupts multiple signaling pathways and leads to the cystic phenotype.

Activation of calcium-inhibitable adenylyl cyclase 6 (AC6) and inhibition of calcium/calmodulin-dependent phosphodiesterase 1 (PDE1) causes abnormal accumulation of cAMP and activation of PKA. Disrupted intracellular calcium homeostasis interferes with aquaporin-2 (AQP-2) targeting to the apical membrane. Sustained PKA activation of PC2 and RyRs makes these channels leaky and leads to reduced intracellular calcium stores, further driving cAMP/PKA signaling. PKA activation also disrupts tubulogenesis, activates proproliferative signaling pathways, stimulates chloride and fluid secretion, and promotes STAT3-induced transcription of chemokines and cytokines. Vasopressin V2 and somatostatin (SST) stimulation of their respective receptors (V2R and SSTR) results in increased cAMP. Gs and Gi refer to guanosine nucleotide-binding proteins s and i, respectively. Yellow indicates proteins that are reduced in PKD; blue indicates proteins that are increased in PKD.

Figure 2. Network of pathways and transcription functions that regulate cell cycle progression, energy metabolism, and cell proliferation and death that are abnormal in PKD.

Upregulation of B-Raf/Mek/ERK, PI3K/AKT, and Wnt/β-catenin pathways and MYC and HIF transcription factors and downregulation of the LKB1/AMPK/TSC pathway, GSK3, and p53 promote aerobic glycolysis and cell cycle progression. Upregulation of MYC and downregulation of p53 exert proapoptotic and antiapoptotic effects, respectively. Downregulation of AMPK stimulates ion transport and fluid secretion. At multiple levels in this network, PKA activity stimulates proproliferative and inhibits antiproliferative signals. Yellow indicates proteins that are reduced in PKD; blue indicates proteins that are increased in PKD. OXPHOS, oxidative phosphorylation.

Figure 3. A model for the contribution of macrophages to PKD progression.

Activation of signaling pathways and transcription factors (e.g., STAT3, NF-κB) in cyst-lining cells stimulates the production and release of chemokines (e.g., MCP-1, osteopontin) attracting monocytes, promoting the polarization of invading monocytes and resident macrophages to a proinflammatory phenotype, and activating Th1 lymphocytes with further release of mediators and tissue damage. Opsonization of apoptotic cells by pentraxin-2 and secretion of IL-10 and TGF-β by immunosuppressive regulatory T cells promote the polarization of macrophages to a proproliferative phenotype, releasing antiinflammatory cytokines that induce cell proliferation. Incomplete epithelial healing, ongoing injury, and release of IL-4 and IL-13 by Th2 lymphocytes promote the polarization of macrophages to a profibrotic phenotype, releasing TGF-β and connective tissue growth factor (CTGF), which induces the differentiation of fibroblasts into collagen-secreting myofibroblasts.