Uroplakins in the lower urinary tract - PubMed (original) (raw)

Uroplakins in the lower urinary tract

Gilho Lee. Int Neurourol J. 2011 Mar.

Abstract

The apical surface of mammalian urinary epithelium is covered by numerous scallop-shaped membrane plaques. This plaque consists of four different uroplakins (UPs) and integral membrane proteins. UPs, which are a member of the tetraspanin superfamily, are assembled into plaques that act as an exceptional barrier to water and toxic materials in urine. Within the plaques, the four UPs are organized into two heterodimers consisting of UP Ia/UP II and UP Ib/UP III in the endoplasmic reticulum. The two heterodimers bind to a heterotetramer, and then assemble into 16-nm particles in the Golgi apparatus. The aggregated UP complex ultimately covers almost all the mature fusiform vesicles in cytoplasm. These organelles migrate towards the apical urothelial cells, where they can fuse with the apical plasma membrane. As a result, the UPs are synthesized in large quantities only by terminally differentiated urothelial cells. For this reason, the UPs can be regarded as a major urothelial differentiation marker. In UP knockout (KO) mice, the incorporation of fully assembled UP plaques in cytoplasm into the apical surface is not functional. The mice with UP III-deficient urothelium show a significantly reduced number of UPs, whereas those with UP II-deficient urothelium have nearly undetectable levels of UPs. This finding strongly suggests that UP II ablation completely abolishes plaque formation. In addition, UP II KO mice contain abnormal epithelial polyps or complete epithelial occlusion in their ureters. UP IIIa KO mice are also associated with impairment of the urothelial permeability barrier and development of vesicoureteral reflux as well as a decrease in urothelial plaque size. In this review, I summarize recently published studies about UPs and attempt to explain the clinical significance of our laboratory results.

Keywords: Animal model; Uroplakin; Urothelium.

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Conflict of interest statement

No potential conflict of interest relevant to this article was reported.

Figures

Fig. 1

Fig. 1

The functional units of mouse uroplakins (UPs) are encoded by separate genes on different chromosomes. The mammalian UPs, including bovine, human, rat, and mouse, are highly conserved.

Fig. 2

Fig. 2

Molecular structures of tetraspanins. Many tetraspanins such as uroplakin Ia, and Ib are typically composed of 4 transmembrane (TM) domains containing several conserved amino acid sequences (Modified from Levy S and Shoham T. Physiology (Bethesda) 2005;20:218-24, with permission American Physiological Society) [17].

Fig. 3

Fig. 3

The mouse uroplakin (UP) II and UP IIIa have a single transmembrane (TM) domain and share a conserved 12 amino acid residues located on the extracellular side and the TM domain (RT/SGGMV/IVITV/SL/IL). Interestingly, UP IIIa is the only UP that has a relatively large cytoplasmic domain of 50 amino acid residues. (Modified from Sun TT. Am J Physiol Renal Physiol 2006;291:F9-21, with permission of American Physiological Society) [20].

Fig. 4

Fig. 4

The mouse uroplakin IIIa and IIIb have 6 exonal structures. The amino acid residues from rat and human uroplakin IIIa and IIIb also share conserved amino acid sequences.

Fig. 5

Fig. 5

Scanning electron microscopic images of normal mouse urinary bladder. The mouse urinary bladder epithelium is covered by numerous scallop-shaped membrane plaques.

Fig. 6

Fig. 6

Uroplakin and β-actin expression on urinary bladder and prostate. Bladder, urinary bladder; VP, ventral prostate; PLP, posterior lateral prostate; Coagulating, coagulating gland (Reprinted from Lee DH and Lee GH. Korean J Androl 2010;28: 112-7, with permission of Korean Society for Sexual Medicine and Andrology) [31].

Fig. 7

Fig. 7

Histological alterations in the cyclophosphamide-induced rat bladder. (A) normal epithelium projected to bladder lumen in controls (H&E, ×40). (B) histologic section of the urinary bladder of mice showing epithelial ulceration, hemorrhage, and submucosal edema at 12 hours after cyclophosphamide injection (H&E, ×10). (C) and (D), cystitis improved at 24 and 72 hours, respectively (H&E, ×10) (Reprinted from Choi SH et al. J Korean Med Sci 2009;24:684-9, with permission of Korean Academy of Medical Sciences) [43].

Fig. 8

Fig. 8

Structural analysis of rat urothelium after 24-hour exposure to 150 mg cyclophosphamide. There are clear-cut areas that are denuded of umbrella cells and intermediate cells can be discerned. Arrows indicate denuded areas.

Fig. 9

Fig. 9

Immunohistochemical reaction with anti-uroplakin III antibody. (A) Strong uroplakin III expression appeared along the bladder epithelium in control bladder. (B) At 12 hours after cyclophosphamide injection, there was a significant decrease or loss of uroplakin III expression in intact bladder mucosa (arrows). (C, D) Expression was weakly restored at 24 hours and completely recovered at 72 hours. All original magnifications were×10.

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