Pkd1 and Pkd2 are required for normal placental development.
BACKGROUND
Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of inherited renal failure that results from mutations in PKD1 and PKD2. The disorder is characterized by focal cyst formation that involves somatic mutation of the wild type allele in a large fraction of cysts. Consistent with a two-hit mechanism, mice that are homozygous for inactivating mutations of either Pkd1 or Pkd2 develop cystic kidneys, edema and hemorrhage and typically die in midgestation. Cystic kidney disease is unlikely to be the cause of fetal loss since renal function is not required to complete gestation. One hypothesis is that embryonic demise is due to leaky vessels or cardiac pathology.


RESULTS
In these studies we used a series of genetically modified Pkd1 and Pkd2 murine models to investigate the cause of embryonic lethality in mutant embryos. Since placental defects are a frequent cause of fetal loss, we conducted histopathologic analyses of placentas from Pkd1 null mice and detected abnormalities of the labyrinth layer beginning at E12.5. We performed placental rescue experiments using tetraploid aggregation and conditional inactivation of Pkd1 with the Meox2 Cre recombinase. We found that both strategies improved the viability of Pkd1 null embryos. Selective inactivation of Pkd1 and Pkd2 in endothelial cells resulted in polyhydramnios and abnormalities similar to those observed in Pkd1(-/-) placentas. However, endothelial cell specific deletion of Pkd1 or Pkd2 did not yield the dramatic vascular phenotypes observed in null animals.


CONCLUSIONS
Placental abnormalities contribute to the fetal demise of Pkd(-/-) embryos. Endothelial cell specific deletion of Pkd1 or Pkd2 recapitulates a subset of findings seen in Pkd null animals. Our studies reveal a complex role for polycystins in maintaining vascular integrity.
Garcia-Gonzalez
Miguel A
MA
Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Outeda
Patricia
P
Zhou
Qin
Q
Zhou
Fang
F
Menezes
Luis F
LF
Qian
Feng
F
Huso
David L
DL
Germino
Gregory G
GG
Piontek
Klaus B
KB
Watnick
Terry
T
D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010920:Placenta / Q000196:embryology* / Q000378:metabolism*; D011247:Pregnancy; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism*
D050396:TRPP Cation Channels