Ablation of uroplakin III gene results in small urothelial plaques, urothelial leakage, and vesicoureteral reflux

Urothelium synthesizes a group of integral membrane proteins called uroplak ins, which form two-dimensional crystals (urothelial plaques) covering >90% of the apical urothelial surface. We show that the ablation of the mouse u roplakin III (UPIII) gene leads to overexpression, defective glycosylation, and abnormal targeting of uroplakin Ib, the presumed partner of UPIII. The UPIII-depleted urothelium features small plaques, becomes leaky, and has e nlarged ureteral orifices resulting in the back flow of urine, hydronephros is, and altered renal function indicators. Thus, UPIII is an integral subun it of the urothelial plaque and contributes to the permeability barrier fun ction of the urothelium, and UPIII deficiency can lead to global anomalies in the urinary tract. The ablation of a single urothelial-specific gene can therefore cause primary vesicoureteral reflux (VUR). a hereditary disease affecting similar to1% Of pregnancies and representing a leading cause of r enal failure in infants. The fact that VUR caused by UPIII deletion seems d istinct from that caused by the deletion of angiotensin receptor II gene su ggests the existence of VUR subtypes. Mutations in multiple gene, including some that are urothelial specific, may therefore cause different subtypes of primary reflux. Studies of VUR in animal models caused by well-defined g enetic defects should lead to improved molecular classification, prenatal d iagnosis, and therapy of this important hereditary problem.