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Impaired glomerulogenesis and endothelial cell migration in Pkd1-deficient renal organ cultures
- Source :
- Biochemical and Biophysical Research Communications
- Publication Year :
- 2014
- Publisher :
- Elsevier BV, 2014.
-
Abstract
- Highlights • The PKD1 gene, mutated in ADPKD is developmentally regulated in the kidney. • Renal organ cultures of two distinct Pkd1 mutants display normal UB branching. • Glomeruli fail to properly develop in Pkd1 mutant renal organ cultures. • Defective endothelial cell migration likely accounts for glomerulogenesis defects. • PI3kinase inhibitors phenocopy the Pkd1 phenotype, VEGF minimally improves it.<br />The PKD1 gene is essential for a number of biological functions, and its loss-of-function causes autosomal dominant polycystic kidney disease (ADPKD). The gene is developmentally regulated and believed to play an essential role in renal development. Previous studies have shown that manipulating murine renal organ cultures with dominant-negative forms of the Pkd1 gene impaired ureteric bud (UB) branching. In the current study, we analyzed different stages of renal development in two distinct mouse models carrying either a null mutation or inactivation of the last two exons of Pkd1. Surprisingly, metanephric explants from Pkd1-deleted kidneys harvested at day E11.5 did not show defects of UB branching and elongation, estimated by cytokeratin staining on fixed tissues or by Hoxb7-GFP time-lapse imaging. However, renal explants from Pkd1-mutants isolated at day E14.5 showed impaired nephrogenesis. Notably, we observed cell migratory defects in the developing endothelial compartment. Previous studies had implicated the Pkd1 gene in controlling cell migration and collagen deposition through PI3 kinases. In line with these studies, our results show that wild-type explants treated with PI3-kinase inhibitors recapitulate the endothelial defects observed in Pkd1 mutants, whereas treatment with VEGF only partially rescued the defects. Our data are consistent with a role for the Pkd1 gene in the endothelium that may be required for proper nephrogenesis.
- Subjects :
- Glomerulogenesis
medicine.medical_specialty
TRPP Cation Channels
Kidney development
Kidney Glomerulus
Biophysics
Autosomal dominant polycystic kidney disease
Endothelial cell migration
Biology
urologic and male genital diseases
Biochemistry
Article
Mice
Organ Culture Techniques
Polycystic kidney disease
Cell Movement
Internal medicine
medicine
Animals
Molecular Biology
Phosphoinositide-3 Kinase Inhibitors
PKD1
urogenital system
Endothelial Cells
Cell migration
Cell Biology
Polycystic Kidney, Autosomal Dominant
medicine.disease
Null allele
female genital diseases and pregnancy complications
Cell biology
Endothelial stem cell
Endocrinology
Ureteric bud
Mutation
embryonic structures
Gene Deletion
Subjects
Details
- ISSN :
- 0006291X
- Volume :
- 444
- Database :
- OpenAIRE
- Journal :
- Biochemical and Biophysical Research Communications
- Accession number :
- edsair.doi.dedup.....d33fcd66e45b2c8031e9557fa1210622