Loss of chloride channel ClC-5 impairs endocytosis by defective trafficking of megalin and cubilin in kidney proximal tubules

Christensen, Erik; Devuyst, Olivier; Dom, Geert; Nielsen, Rikke; Smissen, Patrick Van Der; Verroust, P; Leruth, Michèle; Guggino, William B.; Courtoy, Pierre J.

doi:10.1073/pnas.1432873100

Cited by 289 publications

(332 citation statements)

References 46 publications

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“…We assume that the internalized NaPi-II was degraded after the repeated administration of His-sRAP, although the reduction in the amount of NaPi-II protein was not obvious after a single injection. As previously reported, ClC-5-deficient mice exhibit secondary dysfunction of megalin and a defect in trafficking of NaPi-II (17,18). The findings in our model using His-sRAP together with the observation in ClC-5-deficient mice indicate the involvement of megalin in renal phosphate uptake.…”

Section: Discussionsupporting

confidence: 88%

“…Although it is still not clear which human disease is caused directly by a defect in megalin, some diseases, including Dent's disease and some forms of renal Fanconi syndrome, are reported to be associated with secondary malfunction of megalin (15,16). Reduced apical expression of megalin in the proximal tubules, as well as reduced levels of megalin detected in urine, was demonstrated in a mouse model of Dent's disease (17,18). In addition, some medicines such as antibiotics (aminoglycosides) and anticancer drugs exert a nephrotoxic effect and cause malfunction of renal tubular cells (19,20).…”

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confidence: 99%

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Intraperitoneal Administration of Recombinant Receptor-Associated Protein Causes Phosphaturia via an Alteration in Subcellular Distribution of the Renal Sodium Phosphate Co-Transporter

Yamagata

Ozono

Hashimoto

et al. 2005

Journal of the American Society of Nephrology

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Megalin is a multifunctional endocytic receptor that is expressed in renal proximal tubules and plays critical roles in the renal uptake of various proteins. It was hypothesized that megalin-dependent endocytosis might play a role in renal phosphate reabsorption. For addressing the short-term effects of altered megalin function, a recombinant protein for the soluble form of 39-kD receptor-associated protein (RAP) was administered intraperitoneally to 7-wk-old mice. Histidine (His)-tagged soluble RAP (amino acids 39 to 356) lacking the amino-terminal signal peptide and the carboxy-terminal endoplasmic reticulum retention signal was prepared by bacterial expression (designated His-sRAP). After the direct interaction between His-sRAP and megalin was confirmed, mice were given a single intraperitoneal administration of His-sRAP (3.5 mg/dose). Immunostaining and Western blot analyses demonstrated the uptake of His-sRAP and the accelerated internalization of megalin in proximal tubular cells 1 h after administration. In addition, internalization of the type II sodium/phosphate co-transporter (NaPi-II) was observed. The effects of three sequential administrations of His-sRAP (3.5 mg/dose, three doses at 4-h intervals) then were examined, and increased urinary excretion of low molecular weight proteins, including vitamin D-binding protein, was found, which is consistent with findings reported for megalin-deficient mice. It is interesting that urinary excretion of phosphate was also increased, and the protein level of NaPi-II in the brush border membrane was decreased. Serum concentration of 25-hydroxyvitamin D was decreased, whereas the plasma level of intact parathyroid hormone was not altered by the administration of His-sRAP. The results suggest that the His-sRAP-induced acceleration of megalin-mediated endocytosis caused phosphaturia via altered subcellular distribution of NaPi-II.

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Section: Discussionsupporting

confidence: 88%

mentioning

confidence: 99%

Intraperitoneal Administration of Recombinant Receptor-Associated Protein Causes Phosphaturia via an Alteration in Subcellular Distribution of the Renal Sodium Phosphate Co-Transporter

Yamagata

Ozono

Hashimoto

et al. 2005

Journal of the American Society of Nephrology

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“…This pattern of independent protein regulation of megalin and cubilin has been demonstrated in the same animal model (Christensen et al. 2003). Additional experiments are necessary to understand the differential regulation of megalin and cubilin protein and mRNA expression.…”

Section: Discussionmentioning

confidence: 99%

“…Also, this increase in urinary excretion of transferrin was observed in ClC‐5 KO mice (Christensen et al. 2003). …”

Section: Discussionmentioning

confidence: 99%

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR

et al. 2017

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Diabetic nephropathy (DN) occurs in around 40% of those with diabetes. Proteinuria is the main characteristic of DN and develops as a result of increased permeability of the glomerulus capillary wall and/or decreased proximal tubule endocytosis. The goal of this work was to evaluate renal function and the expression of megalin, cubilin, CFTR (cystic fibrosis transmembrane conductance regulator), and ClC‐5 in the proximal tubule and renal cortex of rats with type 1 diabetes. Male Wistar rats were randomly assigned to control (CTRL) and diabetic (DM) groups for 4 weeks. Renal function was assessed in 24‐h urine sample by calculating clearance and fractional excretion of solutes. The RNA and protein contents of ClC‐5, CFTR, megalin, and cubilin were determined in the renal proximal tubule and cortex using real‐time polymerase chain reaction and western blotting techniques, respectively. The results showed higher creatinine clearance and higher urinary excretion of proteins, albumin, and transferrin in the DM group than in the CTRL group. Furthermore, the renal cortex and proximal tubule of diabetic animals showed downregulation of megalin, cubilin, ClC‐5, and CFTR, critical components of the endocytic apparatus. These data suggest dysfunction in proximal tubule low‐molecular‐weight endocytosis and protein glomerulus filtration in the kidney of diabetic rats.

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“…Another possible role played by ClC-5 is in mediating the protein-protein interactions that are involved in the assembly of the endocytic complex (6). This hypothesis is supported by data from the proximal tubules of ClC-5 knock-out mice and patients with Dent's disease where megalin is down-regulated and the v-H ϩ -ATPase is mistrafficked to the basolateral domain (18,19). It is also clear that albumin uptake involves actin cytoskeleton acting as an anchoring point for the endocytic complex (20 -22), because disruption of the cytoskeleton abolishes albumin uptake (21,23).…”

mentioning

confidence: 83%

Regulation of Albumin Endocytosis by PSD95/Dlg/ZO-1 (PDZ) Scaffolds

Hryciw

Ekberg

Ferguson

et al. 2006

Journal of Biological Chemistry

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The constitutive reuptake of albumin from the glomerular filtrate by receptor-mediated endocytosis is a key function of the renal proximal tubules. Both the Cl ؊ channel ClC-5 and the Na ؉ -H ؉ exchanger isoform 3 are critical components of the macromolecular endocytic complex that is required for albumin uptake, and therefore the cell-surface levels of these proteins may limit albumin endocytosis. This study was undertaken to investigate the potential roles of the epithelial PDZ scaffolds, Na ؉ -H ؉ exchange regulatory factors, NHERF1 and NHERF2, in albumin uptake by opossum kidney (OK) cells. We found that ClC-5 co-immunoprecipitates with NHERF2 but not NHERF1 from OK cell lysate. Experiments using fusion proteins demonstrated that this was a direct interaction between an internal binding site in the C terminus of ClC-5 and the PDZ2 module of NHERF2. In OK cells, NHERF2 is restricted to the intravillar region while NHERF1 is located in the microvilli. Silencing NHERF2 reduced both cell-surface levels of ClC-5 and albumin uptake. Conversely, silencing NHERF1 increased cell-surface levels of ClC-5 and albumin uptake, presumably by increasing the mobility of NHE3 in the membrane and its availability to the albumin uptake complex. Surface biotinylation experiments revealed that both NHERF1 and NHERF2 were associated with the plasma membrane and that NHERF2 was recruited to the membrane in the presence of albumin. The importance of the interaction between NHERF2 and the cytoskeleton was demonstrated by a significant reduction in albumin uptake in cells overexpressing an ezrin binding-deficient mutant of NHERF2. Thus NHERF1 and NHERF2 differentially regulate albumin uptake by mechanisms that ultimately alter the cell-surface levels of ClC-5.

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Loss of chloride channel ClC-5 impairs endocytosis by defective trafficking of megalin and cubilin in kidney proximal tubules

Cited by 289 publications

References 46 publications

Intraperitoneal Administration of Recombinant Receptor-Associated Protein Causes Phosphaturia via an Alteration in Subcellular Distribution of the Renal Sodium Phosphate Co-Transporter

Intraperitoneal Administration of Recombinant Receptor-Associated Protein Causes Phosphaturia via an Alteration in Subcellular Distribution of the Renal Sodium Phosphate Co-Transporter

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR

Regulation of Albumin Endocytosis by PSD95/Dlg/ZO-1 (PDZ) Scaffolds

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