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POLYCYSTIC KIDNEY DISEASE IN 2018

Progress in the understanding of polycystic kidney disease

Nature Reviews Nephrology volume 15, pages 70–72 (2019)Cite this article

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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

  • 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.

  • 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.

  • 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.

  • 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.

  • Expression of MCP1 promotes macrophage accumulation and cystic dilatation; blocking the MCP1 receptor might be an advantageous strategy for the treatment of ADPKD5.

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 or PKD2, which encode polycystin 1 (PC1) and polycystin 2 (PC2), respectively. PC1 and PC2 are generally accepted to form and function as a polycystin complex, but the structure of this complex is unclear. Current evidence suggests that germline and possibly somatic mutations to PKD1 or PKD2 reduce PC1 or PC2 levels below a critical threshold that is required to prevent cyst formation. The functional effect of mutation may be altered G-protein and cAMP signalling, resulting in disruption of downstream signalling pathways and cystogenesis. The immune system may also play a major part in disease progression in ADPKD. Key studies published in 2018 made important contributions to the understanding of these areas1,2,3,4,5.

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Fig. 1: The structure of a PC1–PC2 complex.

References

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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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  1. Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, MN, USA

    Vicente E. Torres & Peter C. Harris

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  1. Vicente E. Torres
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Correspondence to Vicente E. Torres or Peter C. Harris.

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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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