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A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1

Nature Medicine volume 13, pages 1490–1495 (2007)Cite this article

Abstract

Autosomal dominant polycystic kidney disease is an important cause of end-stage renal disease, for which there is no proven therapy1. Mutations in PKD1 (the gene encoding polycystin-1) are the principal cause of this disease. The disease begins in utero2 and is slowly progressive, but it is not known whether cystogenesis is an ongoing process during adult life. We now show that inactivation of Pkd1 in mice before postnatal day 13 results in severely cystic kidneys within 3 weeks, whereas inactivation at day 14 and later results in cysts only after 5 months. We found that cellular proliferation was not appreciably higher in cystic specimens than in age-matched controls, but the abrupt change in response to Pkd1 inactivation corresponded to a previously unrecognized brake point during renal growth and significant changes in gene expression. These findings suggest that the effects of Pkd1 inactivation are defined by a developmental switch that signals the end of the terminal renal maturation process. Our studies show that Pkd1 regulates tubular morphology in both developing and adult kidney, but the pathologic consequences of inactivation are defined by the organ's developmental status. These results have important implications for clinical understanding of the disease and therapeutic approaches.

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Figure 1: Time of inactivation determines renal response to acquired Pkd1 loss.
Figure 2: Susceptibility to rapid-onset cystic disease switches off between P12 and P14.
Figure 3: Abrupt brake point in rate of renal proliferation parallels marked changes in gene expression.

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Acknowledgements

This work was supported by grants from the US National Institutes of Health (DK48006, DK51259) and the US National Kidney Foundation (L.F.M.). G.G.G. is the Irving Blum Scholar of the Johns Hopkins University School of Medicine. The authors wish to thank members of the Germino, Watnick, Montell, Qian and Sutters laboratories (Johns Hopkins University School of Medicine), A. Tousson (University of Alabama at Birmingham) and S. Kuo (Johns Hopkins University School of Medicine) for helpful advice, C. Cheadle (Johns Hopkins Bayview Medical Campus Genomics Core) for assistance with the microarray studies, and M. Knepper (US National Institutes of Health) and J. Hoyer (Children's Hospital of Philadelphia) for the antibodies to aquaporin-2 and Tamm-Horsfall glycoprotein, respectively.

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Authors and Affiliations

  1. Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Ross 958, 720 Rutland Avenue, Baltimore, 21205, Maryland, USA

    Klaus Piontek, Luis F Menezes, Miguel A Garcia-Gonzalez & Gregory G Germino

  2. Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine,

    David L Huso

  3. Suite 851 Broadway Research Building, 735 North Broadway, Baltimore, 21205, Maryland, USA

    David L Huso

  4. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    David L Huso

  5. Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Gregory G Germino

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  1. Klaus Piontek
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  4. David L Huso
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Contributions

K.P. designed and performed the experiments and contributed to the writing of the manuscript. L.F.M. assisted in the experimental design, helped to analyze the histopathology, performed the microarray analyses and assisted in the writing of the manuscript. M.A.G.-G. helped perform the experiments and contributed conceptually to the project. D.L.H. helped with the histopathology. G.G.G. directed the project and wrote the manuscript.

Corresponding author

Correspondence to Gregory G Germino.

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Supplementary Figs. 1–3 and Supplementary Table 1 (PDF 1484 kb)

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Piontek, K., Menezes, L., Garcia-Gonzalez, M. et al. A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1. Nat Med 13, 1490–1495 (2007). https://doi.org/10.1038/nm1675

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