Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss-of-function mutations of the ClC-5 chloride channel lead to Dent's disease, a syndrome characterized by low molecular weight proteinuria, hypercalciuria, and kidney stones. We show that ClC-5 is expressed in renal proximal tubule cells, which normally endocytose proteins passing the glomerular filter. Expression is highest below the brush border in a region densely packed with endocytotic vesicles, where ClC-5 colocalizes with the H+-ATPase and with internalized proteins early after uptake. In intercalated cells of the collecting duct it again localizes to apical intracellular vesicles and colocalizes with the proton pump in alpha-intercalated cells. In transfected cells, ClC-5 colocalizes with endocytosed alpha2-macroglobulin. Cotransfection with a GTPase-deficient rab5 mutant leads to enlarged early endosomes that stain for ClC-5. We suggest that ClC-5 may be essential for proximal tubular endocytosis by providing an electrical shunt necessary for the efficient acidification of vesicles in the endocytotic pathway, explaining the proteinuria observed in Dent's disease.
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PMID:ClC-5, the chloride channel mutated in Dent's disease, colocalizes with the proton pump in endocytotically active kidney cells. 965 42

Loss of function mutations of the renal chloride channel, ClC-5, have been implicated in Dent's disease, a genetic disorder characterized by low weight proteinuria, hypercalciuria, nephrolithasis and, in some cases, eventual renal failure. Recently, our laboratory used an RT-PCR/RACE cloning strategy to isolate an amphibian cDNA from the renal epithelial cell line A6 that had high homology to human ClC-5. We now report a full-length native ClC-5 clone (xClC-5, containing 5' and 3' untranslated regions) isolated by screening a cDNA library from A6 cells that was successfully expressed in Xenopus oocytes. In addition, we compared the properties of xClC-5 and hClC-5 using isogenic constructs of xClC-5 and hClC-5 consisting of the open reading frame subcloned into an optimized Xenopus expression vector. Expression of the full-length "native" xClC-5 clone resulted in large, strongly rectifying, outward currents that were not significantly affected by the chloride channel blockers DIDS, DPC, and 9AC. The anion conductivity sequence was NO-3 > Cl- = I- > HCO-3 >> glutamate for xClC-5 and NO-3 > Cl- > HCO-3 > I- >> glutamate for hClC-5. Reduction of the extracellular pH (pHo) from 7.5 to 5.7 inhibited outward ClC-5 currents by 27 +/- 9% for xClC-5 and 39 +/- 7% for hClC-5. The results indicate that amphibian and mammalian ClC-5 have highly similar functional properties. Unlike hClC-5 and most other ClC channels, expression of xClC-5 in oocytes does not require the removal of its untranslated 5' and 3' regions. Acidic solutions inhibited both amphibian and human ClC-5 currents, opposite to the stimulatory effects of low external pH on other ClC channels, suggesting a possibly distinct regulatory mechanism for ClC-5 channels.
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PMID:Comparison of amphibian and human ClC-5: similarity of functional properties and inhibition by external pH. 1019 59

Dent's disease is an X-linked disorder associated with the urinary loss of low-molecular-weight proteins, phosphate and calcium, which often leads to kidney stones. It is caused by mutations in ClC-5, a renal chloride channel that is expressed in endosomes of the proximal tubule. Here we show that disruption of the mouse clcn5 gene causes proteinuria by strongly reducing apical proximal tubular endocytosis. Both receptor-mediated and fluid-phase endocytosis are affected, and the internalization of the apical transporters NaPi-2 and NHE3 is slowed. At steady state, however, both proteins are redistributed from the plasma membrane to intracellular vesicles. This may be caused by an increased stimulation of luminal parathyroid hormone (PTH) receptors owing to the observed decreased tubular endocytosis of PTH. The rise in luminal PTH concentration should also stimulate the hydroxylation of 25(OH) vitamin D3 to the active hormone. However, this is counteracted by a urinary loss of the precursor 25(OH) vitamin D3. The balance between these opposing effects, both of which are secondary to the defect in proximal tubular endocytosis, probably determines whether there will be hypercalciuria and kidney stones.
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PMID:ClC-5 Cl- -channel disruption impairs endocytosis in a mouse model for Dent's disease. 1109 45

The ClC-5 chloride channel resides mainly in vesicles of the endocytotic pathway and contributes to their acidification. Its disruption in mice entails a broad defect in renal endocytosis and causes secondary changes in calciotropic hormone levels. Inactivating mutations in Dent's disease lead to proteinuria and kidney stones. Possibly by recycling, a small fraction of ClC-5 also reaches the plasma membrane. Here we identify a carboxyl-terminal internalization motif in ClC-5. It resembles the PY motif, which is crucial for the endocytosis and degradation of epithelial Na(+) channels. Mutating this motif increases surface expression and currents about 2-fold. This is probably because of interactions with WW domains, because dominant negative mutants of the ubiquitin-protein ligase WWP2 increased surface expression and currents of ClC-5 only when its PY motif was intact. Stimulating endocytosis by expressing rab5 or its GTPase-deficient Q79L mutant decreased WT ClC-5 currents but did not affect channels with mutated motifs. Similarly, decreasing endocytosis by expressing the inactive S34N mutant of rab5 increased ClC-5 currents only if its PY-like motif was intact. Thus, the endocytosis of ClC-5, which itself is crucial for the endocytosis of other proteins, depends on the interaction of a carboxyl-terminal internalization signal with ubiquitin-protein ligases containing WW domains.
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PMID:An internalization signal in ClC-5, an endosomal Cl-channel mutated in dent's disease. 1111 57

ClC-5 is the Cl- channel that is mutated in Dent's disease, an X-chromosome-linked disease characterized by low molecular weight proteinuria, hypercalciuria, and kidney stones. It is predominantly expressed in endocytically active renal proximal cells. We investigated whether this Cl- channel could also be expressed in intestinal tissues that have endocytotic machinery. ClC-5 mRNA was detected in the rat duodenum, jejunum, ileum, and colon. Western blot analyses revealed the presence of the 83-kDa ClC-5 protein in these tissues. Indirect immunofluorescence studies showed that ClC-5 was mainly concentrated in the cytoplasm above the nuclei of enterocytes and colon cells. ClC-5 partially colocalized with the transcytosed polymeric immunoglobulin receptor but was not detectable together with the brush-border-anchored sucrase isomaltase. A subfractionation of vesicles obtained by differential centrifugation showed that ClC-5 is associated with the vacuolar 70-kDa H+-ATPase and the small GTPases rab4 and rab5a, two markers of early endosomes. Thus these results indicate that ClC-5 is present in the small intestine and colon of rats and suggest that it plays a role in the endocytotic pathways of intestinal cells.
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PMID:Tissue distribution and subcellular localization of the ClC-5 chloride channel in rat intestinal cells. 1120 33

Because proteinuria has been demonstrated in patients with autosomal-dominant polycystic kidney disease (ADPKD), we have investigated whether proteinuria also occurs in the (cy/+) rat, a widely used model for ADPKD. Increased urinary excretion of proteins, in particular of albumin, can be found in 16-wk-old (cy/+) rats, with a gel electrophoresis pattern compatible with a tubular origin of proteinuria. Using FITC-labeled dextran as an in vivo tracer for renal tubular endosomal function, we could show that portions of cyst-lining epithelia from proximal tubules have lost the ability to endocytose, which is necessary for the reabsorption of low-molecular-weight proteins. By immunohistochemistry, the expression of other proteins implicated in endocytosis, such as the chloride channel ClC-5 and the albumin receptor megalin, correlated well with the presence and absence of FITC-dextran in cysts. As an example of growth factor systems possibly being affected by this endocytosis defect, we could detect increased urinary levels of insulin-like growth factor-I protein in (cy/+) animals. These data indicate that proteinuria and albuminuria in the aforementioned rat model for ADPKD are due to a loss of the endocytic machinery in epithelia of proximal tubular cysts. This may also affect the concentration of different growth factors and hormones in cyst fluids and thus modulate cyst development.
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PMID:An endocytosis defect as a possible cause of proteinuria in polycystic kidney disease. 1120

ClC-5 is a chloride channel whose gene mutations have been reported to be associated with X-linked nephrolithiasis (XRN), X-linked recessive hypophosphatemic rickets (XLRH), Dent disease, and idiopathic low-molecular-weight proteinuria (ILMWP) in Japanese children. To establish more efficient screening for CLCN5 abnormalities, we developed a new diagnostic method using reverse transcription and polymerase chain reaction (RT-PCR) of cultured renal tubular cells from the urine of patients. Using this new method, we successfully detected microdeletion of ClC-5 mRNA in a patient and splicing abnormality of the CLCN5 Cl channel.
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PMID:A new approach to mRNA in proximal tubule cells of patients with CLCN5 channelopathy. 1126 75

Dent's disease is an inherited disorder characterized by hypercalciuria, low molecular weight proteinuria, and Fanconi syndrome, which is caused by inactivating mutations in ClC-5, a chloride channel expressed in endosomes of the proximal renal tubule. The role of ClC-5 in the pathogenesis of the hypercalciuria and other myriad manifestations of this disease, however, is largely unknown. New insights from three new transgenic mouse models of Dent's disease, reported in the past year, are discussed.
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PMID:Role of ClC-5 in the pathogenesis of hypercalciuria: recent insights from transgenic mouse models. 1134 7

Mutations in the gene CLCN5 encoding the vesicular chloride channel ClC-5 lead to Dent's disease, an X-linked renal disorder. Dent's disease is characterised by proteinuria, hyperphosphaturia and hypercalciuria, which eventually lead to kidney stones and nephrocalcinosis. As it was unclear how mutations in a chloride channel might cause these symptoms, we and others have generated genetic mouse models to elucidate the underlying pathophysiological mechanisms. We review results obtained from these three mouse models and present new data on endosomal acidification and vitamin D metabolism in ClC-5 knock-out (KO) mice. ClC-5 is expressed in apical endosomes of proximal tubular cells where it co-localizes with endocytosed proteins and the proton ATPase. ClC-5 may provide an electric shunt for the efficient operation of the electrogenic H(+)-ATPase. We confirmed this hypothesis by showing that endosomes from CLCN5 KO mice are acidified at a significantly lower rate than wild-type endosomes. This probably results in the drastic impairment of endocytosis observed in ClC-5 KO mice. Parathyroid hormone (PTH) is filtered into the lumen of the nephron, where it is endocytosed and degraded by proximal tubular cells. The defective endocytosis in ClC-5 KO mice entails an increased luminal concentration of PTH, subsequent stimulation of apical PTH receptors which causes an increased endocytosis of the phosphate transporter NaPi and phosphaturia. We now show that it also results in up-regulation of proximal tubular alpha-hydroxylase that generates the active form of vitamin D from its precursor. We discuss how the primary defect in endocytosis leads via secondary changes in calciotropic hormones to the tertiary symptoms hyperphosphaturia, hypercalciuria and kidney stones.
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PMID:The ClC-5 chloride channel knock-out mouse - an animal model for Dent's disease. 1254 89

Dent's disease is a nephrolithiasis disorder associated with hypercalciuria and low molecular weight proteinuria that is caused by mutations in the voltage-gated chloride channel ClC-5. Because the exact cause of hypercalciuria in this disease is unknown and could come from a renal, intestinal, or bone origin, we have investigated overall calcium handling in the ClC-5 knockout mouse (ClC-5 KO). On a high calcium diet, ClC-5 KO mice had elevated serum 1alpha,25-dihydroxyvitamin D3 (1alpha,25D3), alkaline phosphatase (AP), osteocalcin (OC), and urinary deoxypyridinoline (DPD), but serum parathyroid hormone (PTH), calcium, and intestinal calcium uptake was similar to that of wild-type (WT) mice. A 30-fold decrease in dietary calcium intake caused elevation of serum PTH and urinary cyclic adenosine monophosphate in ClC-5 KO mice and decreased the renal calcium excretion, which still remained 2-fold above that of WT mice. On this low calcium diet, both groups of mice had the same serum 1alpha,25D3, with similar increments in intestinal calcium absorption, serum AP, OC, and urinary DPD. These data indicate that the hypercalciuria in the ClC-5 KO mice on low and high calcium diets is of bone and renal origin and is not caused by increased intestinal calcium absorption, despite an elevated serum 1alpha,25D3. These mice data suggest that young patients with this disease may have a propensity for altered bone homeostasis that should be monitored clinically.
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PMID:The ClC-5 knockout mouse model of Dent's disease has renal hypercalciuria and increased bone turnover. 1267 22


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