Hypertonicity increases CLC-5 expression in mouse medullary thick ascending limb cells

Pham, Phuong‐Chi T.; Devuyst, Olivier; Pham, Phuong‐Thu T.; Matsumoto, Naoko; Shih, Remi N. G.; Jo, Oak D.; Yanagawa, Norimoto; Sun, Ang

doi:10.1152/ajprenal.00229.2003

Cited by 13 publications

(5 citation statements)

References 42 publications

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“…Several studies demonstrate that this expression has a physiological impact. Specifically, an increased ClC-5 expression has been found in mouse medullary thick ascending limb cells under hypertonic conditions ( Pham et al, 2004 ). Moreover, pathophysiological ablation of ClC-5 in human patients resulted in abnormal depletion of H-ATPases from the apical pole of α-type intercalated cells ( Moulin et al, 2003 ).…”

Section: Discussionmentioning

confidence: 99%

Barttin Regulates the Subcellular Localization and Posttranslational Modification of Human Cl-/H+ Antiporter ClC-5

et al. 2018

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Dent disease 1 (DD1) is a renal salt-wasting tubulopathy associated with mutations in the Cl-/H+ antiporter ClC-5. The disease typically manifests with proteinuria, hypercalciuria, nephrocalcinosis, and nephrolithiasis but is characterized by large phenotypic variability of no clear origin. Several DD1 cases have been reported lately with additional atypical hypokalemic metabolic alkalosis and hyperaldosteronism, symptoms usually associated with another renal disease termed Bartter syndrome (BS). Expression of the Bartter-like DD1 mutant ClC-5 G261E in HEK293T cells showed that it is retained in the ER and lacks the complex glycosylation typical for ClC-5 WT. Accordingly, the mutant abolished CLC ionic transport. Such phenotype is not unusual and is often observed also in DD1 ClC-5 mutants not associated with Bartter like phenotype. We noticed, therefore, that one type of BS is associated with mutations in the protein barttin that serves as an accessory subunit regulating the function and subcellular localization of ClC-K channels. The overlapping symptomatology of DD1 and BS, together with the homology between the proteins of the CLC family, led us to investigate whether barttin might also regulate ClC-5 transport. In HEK293T cells, we found that barttin cotransfection impairs the complex glycosylation and arrests ClC-5 in the endoplasmic reticulum. As barttin and ClC-5 are both expressed in the thin and thick ascending limbs of the Henle’s loop and the collecting duct, interactions between the two proteins could potentially contribute to the phenotypic variability of DD1. Pathologic barttin mutants differentially regulated trafficking and processing of ClC-5, suggesting that the interaction between the two proteins might be relevant also for the pathophysiology of BS. Our findings show that barttin regulates the subcellular localization not only of kidney ClC-K channels but also of the ClC-5 transporter, and suggest that ClC-5 might potentially play a role not only in kidney proximal tubules but also in tubular kidney segments expressing barttin. In addition, they demonstrate that the spectrum of clinical, genetic and molecular pathophysiology investigation of DD1 should be extended.

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Section: Discussionmentioning

confidence: 99%

Barttin Regulates the Subcellular Localization and Posttranslational Modification of Human Cl-/H+ Antiporter ClC-5

et al. 2018

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“…The potential roles of ClC-5 in the TAL (involved in the urinary concentration mechanism and the regulated reabsorption of divalent cations) [32] and in the α-type IC (responsible for distal urinary acidification) remain to be defined [33]. Of interest, CLCN5 mutations have not been detected in patients with idiopathic hypercalciuria and in the hypercalciuric stone-forming (GHS) rat strain [34].…”

Section: Pathophysiologymentioning

confidence: 99%

Dent's disease

Devuyst

Thakker

2010

Orphanet J Rare Dis

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195

158

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Dent's disease is a renal tubular disorder characterized by manifestations of proximal tubule dysfunction, including low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, and progressive renal failure. These features are generally found in males only, and may be present in early childhood, whereas female carriers may show a milder phenotype. Prevalence is unknown; the disorder has been reported in around 250 families to date. Complications such as rickets or osteomalacia may occur. The disease is caused by mutations in either the CLCN5 (Dent disease 1) or OCRL1 (Dent disease 2) genes that are located on chromosome Xp11.22 and Xq25, respectively. CLCN5 encodes the electrogenic Cl-/H+ exchanger ClC-5, which belongs to the CLC family of Cl- channels/transporters. OCRL1 encodes a phosphatidylinositol bisphosphate (PIP2) 5-phosphatase and mutations are also associated with Lowe Syndrome. The phenotype of Dent's disease is explained by the predominant expression of ClC-5 in the proximal tubule segments of the kidney. No genotype-phenotype correlation has been described thus far, and there is considerable intra-familial variability in disease severity. A few patients with Dent's disease do not harbour mutations in CLCN5 and OCRL1, pointing to the involvement of other genes. Diagnosis is based on the presence of all three of the following criteria: low-molecular-weight proteinuria, hypercalciuria and at least one of the following: nephrocalcinosis, kidney stones, hematuria, hypophosphatemia or renal insufficiency. Molecular genetic testing confirms the diagnosis. The differential diagnosis includes other causes of generalized dysfunction of the proximal tubules (renal Fanconi syndrome), hereditary, acquired, or caused by exogenous substances. Antenatal diagnosis and pre-implantation genetic testing is not advised. The care of patients with Dent's disease is supportive, focusing on the treatment of hypercalciuria and the prevention of nephrolithiasis. The vital prognosis is good in the majority of patients. Progression to end-stage renal failure occurs between the 3rd and 5th decades of life in 30-80% of affected males.

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“…However, recent data obtained in a cultured TAL murine cell line, as well as in mice exposed to water deprivation, suggest that exposure to hypertonicity upregulates the expression of ClC-5 at the mRNA and protein levels. Thus, the regulation of ClC-5 expression may be crucial for the adaptation to a hypertonic environment and the preservation of correct endocytic activity/targeting in TAL cells [24]. …”

Section: Recent Developments and Perspectivesmentioning

confidence: 99%

Chloride Channels and Endocytosis: New Insights from Dent’s Disease and ClC-5 Knockout Mice

et al. 2005

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Dent’s disease is a hereditary renal tubular disorder characterized by low-molecular weight (LMW) proteinuria, hypercalciuria and nephrolithiasis. The disease is due to mutations of ClC-5, a member of the family of voltage-gated CLC chloride channels. ClC-5 is expressed in part in cells lining the proximal tubule (PT) of the kidney, where it colocalizes with albumin-containing endocytic vesicles belonging to the receptor-mediated endocytic pathway that ensures efficient reabsorption of ultrafiltrated LMW proteins. Since progression along the endocytic apparatus requires endosomal acidification, it has been suggested that dysfunction of ClC-5 in endosomes may lead to inefficient reabsorption of LMW proteins and dysfunction of PT cells. Analysis of a ClC-5 knockout (KO) mouse model, displaying all the characteristic renal tubular defects of Dent’s disease, showed evidence of a severe LMW proteinuria. Cytochemical studies with the endocytic tracer, peroxidase, showed poor transfer into early endocytic vesicles, suggesting that impairment of receptor-mediated endocytosis in PT cells is the basis for the defective uptake of LMW proteins in patients with Dent’s disease. Endocytosis and processing of LMW proteins involve the multiligand tandem receptors, megalin and cubilin, that are abundantly expressed at the brush border of PT cells. Characterization of the endocytic defect in ClC-5 KO mice revealed that ligands of both megalin and cubilin were affected. The total kidney content of megalin and especially cubilin at the protein level was decreased but, more importantly, using analytical subcellular fractionation and quantitative immunogold labelling we demonstrated a selective disappearance of megalin and cubilin at the brush border of PT cells. These observations allowed us to conclude that defective protein endocytosis linked to ClC-5 inactivation is due at least in part to a major and selective loss of megalin and cubilin at the brush border, reflecting a trafficking defect in renal PT cells. These results improve our understanding of Dent’s disease, taken as a paradigm for renal Fanconi syndrome and nephrolithiasis, and demonstrate multiple roles for ClC-5 in the kidney. These studies also provided insights into important functions such as apical endocytosis, handling of proteins by renal tubular cells, calcium metabolism, and urinary acidification.

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Hypertonicity increases CLC-5 expression in mouse medullary thick ascending limb cells

Cited by 13 publications

References 42 publications

Barttin Regulates the Subcellular Localization and Posttranslational Modification of Human Cl-/H+ Antiporter ClC-5

Barttin Regulates the Subcellular Localization and Posttranslational Modification of Human Cl-/H+ Antiporter ClC-5

Dent's disease

Chloride Channels and Endocytosis: New Insights from Dent’s Disease and ClC-5 Knockout Mice

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