TY - JOUR
T1 - Loss of polycystin-1 or polycystin-2 results in dysregulated apolipoprotein expression in murine tissues via alterations in nuclear hormone receptors
AU - Allen, Erica
AU - Piontek, Klaus B.
AU - Garrett-Mayer, Elizabeth
AU - Garcia-Gonzalez, Miguel
AU - Gorelick, Kerry Lee
AU - Germino, Gregory G.
PY - 2006/1/1
Y1 - 2006/1/1
N2 - 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 assays, we determined that the activity of HNF-4α, 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.
AB - 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 assays, we determined that the activity of HNF-4α, 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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U2 - 10.1093/hmg/ddi421
DO - 10.1093/hmg/ddi421
M3 - Article
C2 - 16301212
AN - SCOPUS:29644433444
SN - 0964-6906
VL - 15
SP - 11
EP - 21
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 1
ER -