Letter abstract
Nature Medicine 13, 1490 - 1495 (2007)
Published online: 28 October 2007 | doi:10.1038/nm1675
A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1
Klaus Piontek1, Luis F Menezes1, Miguel A Garcia-Gonzalez1, David L Huso2,3 & Gregory G Germino1,4
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.
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Ross 958, 720 Rutland Avenue, Baltimore, Maryland 21205, USA.
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Suite 851 Broadway Research Building, 735 North Broadway, Baltimore, Maryland 21205, USA.
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Correspondence to: Gregory G Germino1,4 e-mail: ggermino@jhmi.edu
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