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1 Ronald O. Perelman Department of Dermatology and Departments of Pharmacology and Urology, Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, New York 10016; 2 Departments of Medicine and Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; and 3 Laboratory of Cellular Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland 20892
Although water, small
nonelectrolytes, and gases are freely permeable through most biological
membranes, apical membranes of certain barrier epithelia exhibit
extremely low permeabilities to these substances. The role of integral
membrane proteins in this barrier function has been unclear. To study
this problem, we have ablated the mouse gene encoding uroplakin III
(UPIII), one of the major protein subunits in urothelial apical
membranes, and measured the permeabilities of these membranes. Ablation
of the UPIII gene greatly diminishes the amounts of uroplakins on the
apical urothelial membrane (Hu P, Deng FM, Liang FX, Hu CM, Auerbach
AB, Shapiro E, Wu XR, Kachar B, and Sun TT. J Cell Biol 151: 961-972, 2000). Our results indicate that normal mouse
urothelium exhibits high transepithelial resistance and low urea and
water permeabilities. The UPIII-deficient urothelium exhibits a normal transepithelial resistance (normal 2,024 ± 122, knockout
2,322 ± 114 
· cm2; P > 0.5). However, the UPIII-deficient apical membrane has a significantly
elevated water permeability (normal 0.91 ± 0.06, knockout
1.83 ± 0.14 cm/s × 10
5; P < 0.05). The urea permeability of the UPIII-deficient membrane also
increased, although to a lesser extent (normal 2.22 ± 0.24, knockout 2.93 ± 0.31 cm/s × 106;
P = 0.12). These results indicate that reduced
targeting of uroplakins to the apical membrane does not significantly
alter the tight junctional barrier but does double the water
permeability. We provide the first demonstration that integral membrane
proteins contribute to the apical membrane permeability barrier
function of urothelium.
urothelium; uroplakin; permeability; vesicoureteral reflux; knockout
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