Human Molecular Genetics, Vol 8, 247-257, Copyright © 1999 by Oxford University Press
O Devuyst, PT Christie, PJ Courtoy, R Beauwens and RV Thakker
Dent's disease, which is a renal tubular disorder characterized by low
molecular weight proteinuria, hypercalciuria and nephrolithiasis, is
associated with inactivating mutations of the X-linked chloride channel,
CLC-5. However, the manner in which a functional loss of CLC-5 leads to
such diverse renal abnormalities remains to be defined. In order to
elucidate this, we performed studies to determine the segmental expression
of CLC-5 in the human kidney and to define its intracellular distribution.
We raised and characterized antisera against human CLC-5, and identified by
immunoblotting an 83 kDa band corresponding to CLC-5 in human kidney cortex
and medulla. Immunohistochemistry revealed CLC-5 expression in the
epithelial cells lining the proximal tubules and the thick ascending limbs
of Henle's loop, and in intercalated cells of the collecting ducts. Studies
of subcellular human kidney fractions established that CLC-5 distribution
was associated best with that of Rab4, which is a marker of recycling early
endosomes. In addition, confocal microscopy studies using the proximal
tubular cell model of opossum kidney cells, which endogenously expressed
CLC-5, revealed that CLC-5 co-localized with the albumin- containing
endocytic vesicles that form part of the receptor-mediated endocytic
pathway. Thus, CLC-5 is expressed at multiple sites in the human nephron
and is likely to have a role in the receptor-mediated endocytic pathway.
Furthermore, the functional loss of CLC-5 in the proximal tubules and the
thick ascending limbs provides an explanation for the occurrences of low
molecular weight proteinuria and hypercalciuria, respectively. These
results help to elucidate further the patho-physiological basis of the
renal tubular defects of Dent's disease.
ARTICLES
Intra-renal and subcellular distribution of the human chloride channel, CLC-5, reveals a pathophysiological basis for Dent's disease
Division of Nephrology and Cell Unit, Christian de Duve Institute of Cellular Pathology, University of LouvainnMedical School, B-1200 Brussels, Belgium.
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