Obstruction of the urinary tract during fetal development causes congenital obstructive nephropathy, the most common basis of chronic kidney disease and end stage renal disease in children. This disease is usually detected prenatally as hydronephrosis, which is a large distention of the kidney due to accumulation of urine in the renal pelvis. Most cases of congenital obstructive nephropathy are the result of ureteropelvic junction (UPJ) obstructions, with an estimated incidence of 1 in 1000-1500 births, where the stenosis is localized to the upper urinary tract at the connection between the renal pelvis and ureter. Despite affecting so many children, we have a poor understanding of the molecular and morphologic etiology of prenatal UPJ obstructions, with a scarcity of non-surgical animal models. We, and others, have shown the importance of the eight-protein exocyst trafficking complex in regulating critical aspects of polarized epithelial cells, such as tight cel-cell contacts, primary cilia, and cyst and tubule lumen formation. Sec10 is a central component of the exocyst complex, and we have recently generated a new transgenic mouse to analyze in vivo consequences of tissue- specific Sec10 inactivation. We initially crossed this floxed-Sec10 strain with the Ksp-Cre mouse strain to induce the knockout of Sec10 specifically in ureteric bud-derived cells during kidney development. Surprisingly, nearly all the Sec10FL/FL;Ksp-Cre mice died quickly after birth, displaying severe bilateral hydronephrosis with obstructed ureters. Based on our preliminary analysis, we hypothesize that uroepithelial dysfunction caused by the conditional inactivation of the Sec10 gene during mouse development leads to congenital UPJ obstruction and hydronephrosis, sharing the pathogenic hallmarks observed in human disease. We will test this hypothesis through the following Specific Aims: (1) Determine the cellular and molecular basis of the congenital obstructive nephropathy observed in Sec10FL/FL;Ksp-Cre mice. We will use a variety of molecular and immunohistological approaches to characterize the ureter blockage and its timeframe of occurrence in Sec10FL/FL;Ksp-Cre embryos, and to identify abnormalities in uroepithelial cells and surrounding smooth muscle cells. (2) Compare the renal injury in Sec10FL/FL;Ksp-Cre mice with pathological features commonly observed in human congenital obstructive nephropathy. We will analyze mutant kidneys for myofibroblast accumulation, glomerular sclerosis, reduced nephrogenesis, tubular atrophy, inflammation, and interstitial fibrosis. We will also analyze physiological parameters in the newborn mice. Completion of these Aims will better define a unique non-surgical model of congenital obstructive nephropathy that can be highly valuable to a critically understudied area of urinary tract development and disease.
Congenital obstructive nephropathy is the leading cause of chronic kidney disease and end stage renal disease in children, and is caused by blockages in the urinary tract during prenatal development. In this application, we propose to characterize a newly discovered non-surgical animal model of congenital obstructive nephropathy, with the goal of better understanding how this condition develops in utero. This new model will help identify new candidate genes and potential therapies for this deadly pediatric disease.
|Polgar, Noemi; Fogelgren, Ben (2018) Regulation of Cell Polarity by Exocyst-Mediated Trafficking. Cold Spring Harb Perspect Biol 10:|
|Fong, Keith S K; Hufnagel, Robert B; Khadka, Vedbar S et al. (2016) A mutation in the tuft mouse disrupts TET1 activity and alters the expression of genes that are crucial for neural tube closure. Dis Model Mech 9:585-96|
|Lee, Amanda J; Polgar, Noemi; Napoli, Josephine A et al. (2016) Fibroproliferative response to urothelial failure obliterates the ureter lumen in a mouse model of prenatal congenital obstructive nephropathy. Sci Rep 6:31137|
|Ching, Travers; Peplowska, Karolina; Huang, Sijia et al. (2016) Pan-Cancer Analyses Reveal Long Intergenic Non-Coding RNAs Relevant to Tumor Diagnosis, Subtyping and Prognosis. EBioMedicine 7:62-72|
|Seixas, Cecília; Choi, Soo Young; Polgar, Noemi et al. (2016) Arl13b and the exocyst interact synergistically in ciliogenesis. Mol Biol Cell 27:308-20|
|Polgar, Noemi; Lee, Amanda J; Lui, Vanessa H et al. (2015) The exocyst gene Sec10 regulates renal epithelial monolayer homeostasis and apoptotic sensitivity. Am J Physiol Cell Physiol 309:C190-201|
|Fogelgren, Ben; Polgar, Noemi; Lui, Vanessa H et al. (2015) Urothelial Defects from Targeted Inactivation of Exocyst Sec10 in Mice Cause Ureteropelvic Junction Obstructions. PLoS One 10:e0129346|
|Fogelgren, Ben; Zuo, Xiaofeng; Buonato, Janine M et al. (2014) Exocyst Sec10 protects renal tubule cells from injury by EGFR/MAPK activation and effects on endocytosis. Am J Physiol Renal Physiol 307:F1334-41|