ClC-5: role in endocytosis in the proximal tubule

Wang, Yinghong, Cai, Hui, Cebotaru, Liudmila, Hryciw, Deanne H., Weinman, Edward J., Donowitz, Mark, Guggino, Sandra E. and Guggino, William B. (2005) ClC-5: role in endocytosis in the proximal tubule. American Journal of Physiology: Renal Physiology, 289 4: F850-F862. doi:10.1152/ajprenal.00011.2005

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Author Wang, Yinghong
Cai, Hui
Cebotaru, Liudmila
Hryciw, Deanne H.
Weinman, Edward J.
Donowitz, Mark
Guggino, Sandra E.
Guggino, William B.
Title ClC-5: role in endocytosis in the proximal tubule
Journal name American Journal of Physiology: Renal Physiology   Check publisher's open access policy
ISSN 0363-6127
Publication date 2005-10-01
Sub-type Article (original research)
DOI 10.1152/ajprenal.00011.2005
Open Access Status File (Author Post-print)
Volume 289
Issue 4
Start page F850
End page F862
Total pages 13
Place of publication Bethesda, MD
Publisher American Physiological Society
Language eng
Subject 270104 Membrane Biology
0601 Biochemistry and Cell Biology
Abstract The proper functioning of the Cl- channel, ClC-5, is essential for the uptake of low molecular mass proteins through receptor-mediated endocytosis in the proximal tubule. Dent's disease patients with mutant ClC-5 channels and ClC-5 knockout ( KO) mice both have low molecular mass proteinuria. To further understand the function of ClC-5, endocytosis was studied in LLC-PK1 cells and primary cultures of proximal tubule cells from wild-type (WT) and ClC-5 KO kidneys. Endocytosis in the proximal tubule cells from KO mice was reduced compared with that in WT animals. Endocytosis in WT but not in KO cells was inhibited by bafilomycin A-1 and Cl- depletion, whereas endocytosis in both WT and KO cells was inhibited by the NHE3 blocker, S3226. Infection with adenovirus containing WT ClC-5 rescued receptor-mediated endocytosis in KO cells, whereas infection with any of the three disease-causing mutants, myc-W22G-ClC5, myc-S520P-ClC-5, or myc-R704X-ClC-5, did not. WT and the three mutants all trafficked to the apical surface, as assessed by surface biotinylation. WT-ClC-5 and the W22G mutant were internalized similarly, whereas neither the S520P nor the R704X mutants was. These data indicate that ClC-5 is important for Cl- and proton pump-mediated endocytosis. However, not all receptor-mediated endocytosis in the proximal tubule is dependent on ClC-5. There is a significant fraction that can be inhibited by an NHE3 blocker. Our data from the mutants suggest that defective targeting and trafficking of mutant ClC-5 to the endosomes are a major determinant in the lack of normal endocytosis in Dent's disease.
Keyword Physiology
Urology & Nephrology
knockout mice
Na-H exchanger type 3
bafilomycin A-1
Receptor-mediated Endocytosis
Renal Chloride Channel
Endosomal Acidification
Functional Expression
Albumin Endocytosis
Impairs Endocytosis
Ok Cells
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

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Created: Sat, 26 Jan 2008, 02:39:17 EST