Ablation of uroplakin III gene results in small urothelial plaques, urothelial leakage, and vesicoureteral reflux
Ablation of uroplakin III gene results in small urothelial plaques, urothelial leakage, and vesicoureteral reflux
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DOI：
10.1083/jcb.151.5.961
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发表时间：
2000-11-27
影响因子：
7.8
通讯作者：
Sun, TT
中科院分区：
文献类型：
--
作者：
Hu, P;Deng, FM;Sun, TT
尿路上皮合成一组称为尿斑蛋白的膜蛋白，其形成覆盖>90%的顶端尿路上皮表面的二维晶体（尿路上皮斑）。我们发现，小鼠尿斑蛋白III（UPIII）基因的消融导致过表达，糖基化缺陷，和尿斑蛋白Ib，推定的合作伙伴UPIII的异常靶向。缺乏UPIII的尿路上皮以小斑块为特征，变得渗漏，输尿管口扩大，导致尿液回流，肾积水和肾功能指标改变。因此，UPIII是尿路上皮斑块的组成亚单位，并有助于尿路上皮的渗透屏障功能，UPIII缺乏可导致泌尿道的整体异常。因此，单个尿路特异性基因的消融可引起原发性膀胱输尿管反流（VUR）。一种遗传性疾病，大约1%的孕妇患病，是婴儿肾衰竭的主要原因。由UPIII缺失引起的VUR似乎与由血管紧张素受体II基因缺失引起的VUR不同，这一事实表明VUR亚型的存在。因此，多个基因突变，包括一些尿路上皮特异性基因突变，可能导致不同亚型的原发性反流。明确的遗传缺陷引起的VUR动物模型的研究应导致改进的分子分类，产前诊断和治疗这一重要的遗传问题。
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.