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Am J Physiol Renal Physiol (February 8, 2005). doi:10.1152/ajprenal.00008.2005
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Submitted on January 12, 2005
Accepted on February 1, 2005

Mispolarization of Desmosomal Proteins and Altered Intercellular Adhesion in Autosomal Dominant Polycystic Kidney Disease

Melina Silberberg1, Audra J. Charron1, Robert Bacallao2, and Angela Wandinger-Ness1*

1 Department of Pathology, University of New Mexico, Albuquerque, NM, USA
2 Department of Nephrology, University of Indianapolis, Indianapolis, IN, USA

* To whom correspondence should be addressed. E-mail: wness{at}unm.edu.

Polycystin-1, the product of the major gene mutated in autosomal dominant polycystic kidney disease (ADPKD), has been shown to associate with multiple epithelial cell junctions. Our hypothesis is that polycystin-1 is an important protein for the initial establishment of cell-cell junctions and maturation of the cell and that polycystin-1 localization is dependent on the degree of cell polarization. Using laser scanning confocal microscopy and two models of cell polarization, polycystin-1 and desmosomes were found to colocalize during the initial establishment of cell-cell contact when junctions were forming. However, colocalization was lost in confluent monolayers. Parallel morphological and biochemical evaluations revealed a profound mispolarization of desmosomal components to both the apical and basolateral domains in primary ADPKD cells and tissue. Studies of the intermediate filament network associated with desmosomes showed that there is a decrease in cytokeratin levels and an abnormal expression of the mesenchymal protein vimentin in the disease. Moreover, we show for the first time that the structural alterations seen in adherens and desmosomal junctions have a functional impact, leaving the ADPKD cells with weakened cell-cell adhesion. In conclusion, in this paper we show that polycystin-1 transiently colocalizes with desmosomes and that desmosomal proteins are mislocalized as a consequence of polycystin-1 mutation.




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