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Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease
Peter C. Harris, Vicente E. Torres
Peter C. Harris, Vicente E. Torres
Published June 2, 2014
Citation Information: J Clin Invest. 2014;124(6):2315-2324. https://doi.org/10.1172/JCI72272.
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Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease

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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.

Authors

Peter C. Harris, Vicente E. Torres

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Figure 1

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

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An abnormal crosstalk of calcium and cAMP signaling disrupts multiple si...
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.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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