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Human Molecular Genetics Advance Access published online on November 21, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi421
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received September 26, 2005
Revised November 7, 2005
Accepted November 7, 2005

Article

Loss of polycystin-1 or polycystin-2 results in dysregulated apolipoprotein expression in murine tissues via alterations in nuclear hormone receptors

Erica Allen 1, Klaus B. Piontek 1, Elizabeth Garrett-Mayer 2, Miguel Garcia-Gonzalez 1, Kerry Lee Gorelick 1, and Gregory G. Germino 3 *

1 Department of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, 21205 USA
2 Department of Oncology, Division of Biostatistics, Johns Hopkins University School of Medicine, Baltimore 21205 USA
3 Department of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Building 9S, Baltimore, MD 21205, USA

* To whom correspondence should be addressed.
Gregory G. Germino, E-mail: ggermino{at}jhmi.edu


  Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations of PKD1 and PKD2. Murine gene targeting studies have shown that these genes play an essential role in development, with homozygous inactivation resulting in embryonic lethality. Recently, Pkd1-/- lethality has been linked to placental insufficiency. In this study, the placenta was used as a model to identify factors involved in these developmental abnormalities. Microarray analysis of Pkd1-/- placentae showed upregulation of a set of apolipoprotein-related genes. These changes were validated and were found to be associated with increased quantities of apolipoproteins in the amniotic fluid. Increased apolipoprotein gene expression was also observed in Pkd2-/- placentae and in cystic kidneys of Pkd1cond/-; Meox2cre/+ mice. Using chromatin immunoprecipitation (ChIP) assays, we determined that the activity of HNF-4{alpha}, a major regulator of apolipoprotein gene expression, was also increased in these organs. These findings suggest a potential role for dysregulation of nuclear hormone receptors in the pathogenesis of ADPKD.


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