Exocyst Dysfunction Impairs Urothelial Development Resulting in Congenital Ureter Obstruction

Abstract

Hydronephrosis is the most commonly detected abnormality in prenatal ultrasounds. The most Prevalent cause of prenatal hydronephrosis is congenital obstructive nephropathy, with obstructions at the ureteropelvic junction (UPJ) region as the most common site for obstruction. The cause and developmental process of obstruction formation at the UPJ is poorly understood. We developed a Sec10 conditional knockout (Sec10-CKO) mouse model where Sec10, a critical subunit of the exocyst complex, has been knocked out in the urothelium that lines the ureter. Sec10-CKO embryos develop complete bilateral UPJ obstructions and hydronephrosis by day 18.5 of gestation (E18.5). Using this model, we were able to study the development of prenatal hydronephrosis. We determined that the urothelium lining the ureters of Sec10-CKO mice fails to differentiate, with the earliest evidence of this starting at E16.5. Loss of key terminal differentiation markers, including uroplakins, weakens the urothelial barrier that prevents urine from permeating into ureter tissues. Our data suggests that a luminal wound healing response at the UPJ starts at E17.5, which would correspond with the time point urine first starts to flow. We measured three characteristics consistent with a fibrotic wound healing response: (1) increased expression of TGFβ1, a key regulator of wound healing and fibrosis, (2) gene expression profiles consistent with myofibroblast activation, with increased proliferation at the site of obstruction, and (3) evidence of stromal remodeling. Our findings support a model where prenatal UPJ obstructions may be caused by an impaired urothelial barrier that allows urine to permeate and damage tissues lining the lumen, inducing a fibrotic wound healing response.