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Pkd1 and Pkd2 are required for normal placental development.
Miguel A Garcia-Gonzalez1, Patricia Outeda, Qin Zhou
1Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Plos One
|September 24, 2010
Summary
Placental defects contribute to embryonic lethality in autosomal dominant polycystic kidney disease (ADPKD) models. Polycystin mutations impact vascular integrity, leading to fetal demise.
Area of Science:
- Genetics
- Developmental Biology
- Nephrology
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited renal failure cause.
- Mutations in PKD1 and PKD2 genes underlie ADPKD, leading to cyst formation.
- Murine models with Pkd1 or Pkd2 mutations exhibit embryonic lethality, suggesting causes beyond renal failure.
Purpose of the Study:
- Investigate the cause of embryonic lethality in Pkd1 and Pkd2 mutant mouse models.
- Determine the role of placental development and vascular integrity in ADPKD-related fetal loss.
Main Methods:
- Utilized genetically modified Pkd1 and Pkd2 murine models.
- Performed histopathologic analyses of placentas from Pkd1 null mice.
- Conducted placental rescue experiments (tetraploid aggregation, conditional inactivation).
- Examined endothelial cell-specific deletion of Pkd1 and Pkd2.
Main Results:
- Detected placental labyrinth layer abnormalities in Pkd1 null embryos starting at E12.5.
- Placental rescue strategies improved the viability of Pkd1 null embryos.
- Selective inactivation of Pkd1/PKD2 in endothelial cells caused polyhydramnios and placental abnormalities.
- Endothelial cell-specific deletion did not fully replicate the vascular phenotypes of null animals.
Conclusions:
- Placental abnormalities are a significant factor in the fetal demise of Pkd mutant embryos.
- Polycystins play a crucial role in maintaining vascular integrity during embryonic development.
- These findings reveal a complex function of polycystins in vascular health.
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