Disruption of clc-5 leads to a redistribution of annexin A2 and promotes calcium crystal agglomeration in collecting duct epithelial cells |
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Authors: | G Carr N L Simmons J A Sayer |
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Institution: | (1) Institute for Cell and Molecular Biosciences, Medical School, University of Newcastle upon Tyne, NE2 4HH Newcastle upon Tyne, United Kingdom;(2) School of Clinical Medical Sciences, Medical School, University of Newcastle upon Tyne, NE2 4HH Newcastle upon Tyne, United Kingdom |
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Abstract: | Mutations in CLCN5, which encodes the voltage-dependent Cl−/H+antiporter, CLC-5, cause Dent’s disease. This disorder is characterized by low molecularweight proteinuria, hypercalciuria,
nephrocalcinosis and nephrolithiasis. Using a collecting duct cell model (mIMCD-3) in which endogenous clc-5 is disrupted
by antisense clc-5 or overexpression of truncated clc-5, we demonstrate altered expression of the crystal adhesion molecule, annexin A2. Endogenously expressed annexin A2 is intracellular
with limited plasma membrane localization. Following clc-5 disruption, there is both a marked increase in plasma membrane
annexin A2 and an increase in cell surface crystal retention and agglomeration, which may be attenuated using pretreatment
with anti-annexin A2 antibodies or wheat germ agglutinin lectin but not by concanavalin A. We hypothesize that in Dent’s disease,
endocytic failure leads to an accumulation at the plasma membrane of crystal-binding molecules that include annexin A2 leading
to retention of calcium crystals and ultimately nephrocalcinosis and nephrolithiasis.
Received 22 October 2005; received after revision 26 November 2005; accepted 2 December 2005 |
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Keywords: | Collecting duct Dent’ s disease kidney stones renal epithelial cell endocytosis nephrocalcinosis |
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