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

被引:196
作者
Hu, P
Deng, FM
Liang, FX
Hu, CM
Auerbach, AB
Shapiro, E
Wu, XR
Kachar, B
Sun, TT
机构
[1] NYU, Sch Med,Kaplan Comprehens Canc Ctr, Ronald O Perelman Dept Dermatol, Epithelial Biol Unit, New York, NY 10016 USA
[2] NYU, Sch Med, Kaplan Comprehens Canc Ctr, Dept Pharmacol, New York, NY 10016 USA
[3] NYU, Sch Med, Kaplan Comprehens Canc Ctr, Skirball Inst Biomol Med, New York, NY 10016 USA
[4] NYU, Sch Med, Kaplan Comprehens Canc Ctr, Dept Urol, New York, NY 10016 USA
[5] NYU, Sch Med, Kaplan Comprehens Canc Ctr, Dept Microbiol, New York, NY 10016 USA
[6] Vet Adm Med Ctr, New York, NY 10010 USA
[7] Natl Inst Deafness & Other Commun Disorders, Sect Struct Cell Biol, NIH, Bethesda, MD 20892 USA
关键词
urothelium; permeability; knockout mice; vesicoureteral reflux; hydronephrosis;
D O I
10.1083/jcb.151.5.961
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Urothelium synthesizes a group of integral membrane proteins called uroplakins, which form two-dimensional crystals (urothelial plaques) covering >90% of the apical urothelial surface. We show that the ablation of the mouse uroplakin 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 enlarged ureteral orifices resulting in the back flow of urine, hydronephrosis, and altered renal function indicators. Thus, UPIII is an integral subunit of the urothelial plaque and contributes to the permeability barrier function 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 renal failure in infants. The fact that VUR caused by UPIII deletion seems distinct from that caused by the deletion of angiotensin receptor II gene suggests 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 genetic defects should lead to improved molecular classification, prenatal diagnosis, and therapy of this important hereditary problem.
引用
收藏
页码:961 / 971
页数:11
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