The function of polycystin proteins and the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) are not well understood. Studies published in 2018 made important contributions to the understanding of genetic mechanisms, the structure of the polycystin complex and the roles of G-protein signalling and the immune system in ADPKD.
Key advances
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The identification of high levels of somatic mutations in PKD1 and PKD2 in autosomal dominant polycystic kidney disease (ADPKD) cysts demonstrates an important role of polycystin loss in cyst progression1.
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A high-resolution cryogenic electron microscopy structure of the polycystin 1–polycystin 2 (PC1–PC2) complex provides insights into polycystin function and suggests that this complex does not form a functional Ca2+ permeable channel2.
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PC1 acts as a G-protein coupled receptor (GPCR) that binds α subunits; loss of the G-protein binding domain of PC1 causes GPCR hyper-reactivity, suggesting possible treatment options for ADPKD3.
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Cilia actively promote chemokine signalling and inflammation via a pathway that promotes monocyte chemoattractant protein 1 (MCP1) expression; this pathway can be suppressed by a module involving LKB1, PC1 and nephronophthisis-associated proteins4.
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Expression of MCP1 promotes macrophage accumulation and cystic dilatation; blocking the MCP1 receptor might be an advantageous strategy for the treatment of ADPKD5.
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References
Tan, A. Y. et al. Somatic mutations in renal cyst epithelium in autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 29, 2139–2156 (2018).
Su, Q. et al. Structure of the human PKD1-PKD2 complex. Science 361, eaat9819 (2018).
Zhang, B., Tran, U. & Wessely, O. Polycystin 1 loss of function is directly linked to an imbalance in G-protein signaling in the kidney. Development 145, dev158931 (2018).
Viau, A. et al. Cilia-localized LKB1 regulates chemokine signaling, macrophage recruitment, and tissue homeostasis in the kidney. EMBO J. 37, e98615 (2018).
Cassini, M. F. et al. Mcp1 promotes macrophage-dependent cyst expansion in autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 29, 2471–2481 (2018).
Trujillano, D. et al. Diagnosis of autosomal dominant polycystic kidney disease using efficient PKD1 and PKD2 targeted next-generation sequencing. Mol. Genet. Genomic Med. 2, 412–421 (2014).
Shen, P. S. et al. The structure of the polycystic kidney disease channel PKD2 in lipid nanodiscs. Cell 167, 763–773 (2016).
Parnell, S. C. et al. A mutation affecting polycystin-1 mediated heterotrimeric G-protein signaling causes PKD. Hum. Mol. Genet. 27, 3313–3324 (2018).
Messchendorp, A. L. et al. Urinary biomarkers to identify autosomal dominant polycystic kidney disease patients with a high likelihood of disease progression. Kidney Int. Rep. 3, 291–301 (2017).
Grantham, J. J. et al. Tolvaptan suppresses monocyte chemotactic protein-1 excretion in autosomal-dominant polycystic kidney disease. Nephrol. Dial. Transplant. 32, 969–975 (2017).
Acknowledgements
The authors’ work is supported by the Mayo Clinic Robert M. and Billie Kelley Pirnie Translational Polycystic Kidney Disease Center and the National Institute of Diabetes and Digestive and Kidney Diseases grant DK090728.
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Torres, V.E., Harris, P.C. Progress in the understanding of polycystic kidney disease. Nat Rev Nephrol 15, 70–72 (2019). https://doi.org/10.1038/s41581-018-0108-1
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DOI: https://doi.org/10.1038/s41581-018-0108-1
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