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Human Molecular Genetics Advance Access published online on April 2, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp147
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Renal Injury is a Third Hit Promoting Rapid Development of Adult Polycystic Kidney Disease

Ayumi Takakura1, Leah Contrino1, Xiangzhi Zhou2, Joseph V. Bonventre1, Yanping Sun2, Benjamin D. Humphreys1 and Jing Zhou1,*

1 Renal Division, Department of Medicine, Boston, Massachusetts 02115, USA 2 Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA

* To whom correspondence should be addressed: Jing Zhou, M.D., Ph.D., Harvard Institutes of Medicine, Room 522, Brigham and Women's Hospital and Harvard Medical School, 4 Blackfan Circle, Boston, Massachusetts 02115, USA, Tel: 617-525-5860, Fax: 617-525-5861, Email: zhou{at}rics.bwh.harvard.edu

Received December 19, 2008; Revised March 20, 2009; Accepted March 20, 2009

The "two-hit" model is a widely accepted genetic mechanism for progressive cyst formation in autosomal dominant polycystic kidney disease. We have previously shown that adult inactivation of Pkd1 using the Mx1Cre+allele causes a late onset of focal cystic disease. An explanation for the delayed appearance of cysts is the requirement for an additional independent factor, or "third hit". Here we show that renal injury leads to massive cystic disease in the same mouse line. Cysts are labeled with a collecting duct/tubule marker, Lectin Dolichos biflorus Agglutinin, which correlates with the site of Cre-mediated recombination in the collecting system. BrdU labeling reveals that cyst-lining epithelial cells are comprised of regenerated cells in response to renal injury. These data demonstrate, for the first time, a role for polycystin-1 in kidney injury and repair and indicate that renal injury constitutes a "third hit" resulting in rapid cyst formation in adulthood.


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