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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Ubiquitination regulates the plasma membrane expression of renal UT-A urea transporters

Faculty of Life Sciences, Core Technology Facility, University of Manchester, Manchester, United Kingdom

Submitted 24 September 2007 ; accepted in final form 23 April 2008

The renal UT-A urea transporters UT-A1, UT-A2, and UT-A3 are known to play an important role in the urinary concentrating mechanism. The control of the cellular localization of UT-A transporters is therefore vital to overall renal function. In the present study, we have investigated the effect of ubiquitination on UT-A plasma membrane expression in Madin-Darby canine kidney (MDCK) cell lines expressing each of the three renal UT-A transporters. Inhibition of the ubiquitin-proteasome pathway caused an increase in basal transepithelial urea flux across MDCK-rat (r)UT-A1 and MDCK-mouse (m)UT-A2 monolayers (P < 0.01, n = 3, ANOVA) and also increased dimethyl urea-sensitive, arginine vasopressin-stimulated urea flux (P < 0.05, n = 3, ANOVA). Inhibition of the ubiquitin-proteasome pathway also increased basolateral urea flux in MDCK-mUT-A3 monolayers (P < 0.01, n = 4, ANOVA) in a concentration-dependent manner. These increases in urea flux corresponded to a significant increase in UT-A transporter expression in the plasma membrane (P < 0.05, n = 3, ANOVA). Further analysis of the MDCK-mUT-A3 cell line confirmed that vasopressin specifically increased UT-A3 expression in the plasma membrane (P < 0.05, n = 3, ANOVA). However, preliminary data suggested that vasopressin produces this effect through an alternative route to that of the ubiquitin-proteasome pathway. In conclusion, our study suggests that ubiquitination regulates the plasma membrane expression of all three major UT-A urea transporters, but that this is not the mechanism primarily used by vasopressin to produce its physiological effects.

ubiquitin-proteasome pathway; urea transport; membrane localization

This article has been cited by other articles:

				G. Chen, H. Huang, O. Frohlich, Y. Yang, J. D. Klein, S. R. Price, and J. M. Sands MDM2 E3 ubiquitin ligase mediates UT-A1 urea transporter ubiquitination and degradation Am J Physiol Renal Physiol, November 1, 2008; 295(5): F1528 - F1534. [Abstract] [Full Text] [PDF]