Pkd1 and Pkd2 Are Required for Normal Placental Development

Abstract

BackgroundAutosomal 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.Methodology/Principal FindingsIn 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/SignificancePlacental 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.

Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease

“…These findings support the observed endothelial dysfunction and reduced nitric oxide generation in ADPKD patients, as well as an increased contractile response of the arterial vasculature in Pkd2 +/-mice (34). A more recent study, in addition, showed that polycystins play a complex role in the maintenance of vascular integrity and that Pkd1 and Pkd2 are necessary for the normal development of the placenta in mice (35).…”

Polycystin Signaling Is Required for Directed Endothelial Cell Migration and Lymphatic Development

“…We detected a similar defect, albeit milder, in embryos with selective endothelial cell deletion of Pkd2 (Pkd2 cond/cond ; Tie2-Cre + aka Pkd2 endo- ) (Figure 5C, 5G-5I). We have previously demonstrated that Tie2-Cre mediated deletion of Pkd1 or Pkd2 in endothelial cells only partially recapitulates the vascular phenotype observed in null animals (Garcia-Gonzalez et al, 2010). Specifically, Pkd2 endo- embryos lack detectable edema and when we analyzed the lymphatic vessels in these mice at E14.5, we found no difference in comparison to controls (Figure S5).…”

Translational value of animal models of kidney failure

“…hemorrhage) or cardiac failure. Studies by our group, however, suggest that placental insufficiency is the predominant factor responsible for this outcome (Garcia-Gonzalez et al, 2010). Similar to homozygous mice, humans with homozygous incompletely penetrant mutations may present with massive PKD in utero (Vujic et al, 2010).…”