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A Novel Transgenic Mouse Model for Congenital Obstructive Nephropathy
Author(s) -
Lee Amanda,
Polgar Noemi,
Lui Vanessa,
Tamashiro KadeeKalia,
Napoli Josephine Andrea,
Lipschutz Joshua,
Fogelgren Ben
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.663.16
Subject(s) - exocyst , neural crest , renal pelvis , ureter , conditional gene knockout , knockout mouse , microbiology and biotechnology , biology , genetically modified mouse , pathology , mesonephric duct , transgene , cancer research , medicine , endocrinology , kidney , urology , phenotype , exocytosis , embryo , receptor , genetics , secretion , gene
Congenital obstructive nephropathy (CON) is the most common cause of chronic kidney disease and end stage renal disease among infants and children. The most common cause of CON is obstruction of the upper ureter at the ureteropelvic junction (UPJ), where the renal pelvis transitions into the ureter. Studying prenatal UPJ obstructions is difficult because the causes are unknown and there are no non‐surgical animal models that recapitulate the disease's development in utero . The protein Sec10 is a central component of the eight‐protein exocyst complex that some cells use to regulate polarized exocytosis of specialized subsets of proteins to the plasma membrane. We have created a Sec10 conditional knockout mouse model, the first conditional allele for any exocyst component. Sec10 inactivation in ureteric bud derived epithelial cells with the Ksp‐Cre mouse strain resulted in bilateral hydronephrosis, complete anuria, and neonatal death. Embryonic analyses of Sec10 conditional knockout mice (Sec10‐CKO) show obstructions develop at the UPJ between E17.5 and E18.5. Immunohistochemical analyses of ureter cross‐sections show the blockage occurs because of a breakdown of the urothelial layer and an overgrowth of the surrounding mesenchymal cells. The Sec10‐knockout urothelial cells failed to maintain a uroplakin barrier, suggesting the exocyst is necessary for uroplakin trafficking. Our results suggest that Sec10 and the exocyst are important in the establishment and maintenance of the urothelial barrier, and breakdown of this urothelial barrier may be a major factor in human CON and UPJ obstructions.