Impaired glomerulogenesis and endothelial cell migration in Pkd1-deficient renal organ cultures

Isaline Rowe, Marco Chiaravalli, Klaus B. Piontek, Gregory G. Germino, Alessandra Boletta

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)473-479
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume444
Issue number4
DOIs
StatePublished - Feb 21 2014

Keywords

  • Endothelial cell migration
  • Glomerulogenesis
  • Kidney development
  • Polycystic kidney disease

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology

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