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Human Molecular Genetics Advance Access published online on April 28, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp190
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Toxic tubular injury in kidneys from Pkd1-deletion mice accelerates cystogenesis accompanied by dysregulated planar cell polarity and canonical Wnt signaling pathways

Hester Happé1, Wouter N. Leonhard1, Annemieke van der Wal2, Bob van de Water3, Irma S. Lantinga-van Leeuwen1, Martijn H. Breuning1, Emile de Heer2 and Dorien J.M. Peters1,*

1 Departments of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, he Netherlands 2 Departments of Pathology, Leiden University Medical Center, 2300 RC Leiden, he Netherlands 3 Division of Toxicology, Leiden Amsterdam Center for Drug Research, 2300  RA Leiden University, Leiden, he Netherlands

* Corresponding author: Dorien J.M. Peters, Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands, Fax: +31-71- 5268285, Phone: +31-71-5269490, E-mail: d.j.m.peters{at}lumc.nl

Received December 22, 2008; Revised April 23, 2009; Accepted April 23, 2009

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by large fluid-filled cysts and progressive deterioration of renal function necessitating renal replacement therapy.

Previously we generated a tamoxifen-inducible, kidney epithelium-specific Pkd1-deletion mouse model and showed that inactivation of the Pkd1 gene induces rapid cyst formation in developing kidneys and a slow onset of disease in adult mice.

Therefore, we hypothesized that injury-induced tubular epithelial cell proliferation may accelerate cyst formation in the kidneys of adult Pkd1-deletion mice.

Mice were treated with the nephrotoxicant DCVC after Pkd1-gene inactivation, which indeed accelerated cyst formation significantly. After the increased proliferation during tissue regeneration, proliferation decreased to basal levels in Pkd1 deletion mice just as in DCVC-treated controls. However, in severe cystic kidneys, 10-14 weeks after injury, proliferation increased again. This biphasic response suggests that unrestricted cell proliferation after injury is not the underlying mechanism for cyst formation. Aberrant Planar Cell Polarity (PCP) signaling and increased canonical Wnt signaling are suggested to be involved in cyst formation. Indeed we show here that in Pkd1 conditional deletion mice expression of the PCP component Four-jointed (Fjx1) is decreased while its expression is required during tissue regeneration. In addition, we show that altered centrosome position and activation of canonical Wnt signaling are early effects of Pkd1 gene disruption. This suggests that additional stimuli or events are required to trigger the process of cyst formation. We propose that during tissue repair the integrity of the newly formed Pkd1-deficient cells is modified rendering them susceptible to subsequent cyst formation.


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