Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020438 (hypercalciuria)
 2,502 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In-vitro calcium influx was measured in jejunal biopsy specimens from 10 men with idiopathic hypercalciuria. Calcium uptake in these adults was a passive process which was not sensitive to inhibition by 2,4 dinitrophenol and sodium fluoride, and showed no evidence of carrier saturation. In 7 of 10 patients with idiopathic hypercalciuria calcium uptake was above the normal range, and the mean uptake for all patients was significantly higher than in 10 control subjects (p < 0.01). The kinetic features suggest that this increased influx was the result of increased brush border permeability to calcium ions.
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PMID:In-vitro calcium uptake by jejunal biopsy specimens from patients with idiopathic hypercalciuria. 610 53

Using an in vitro method, the uptake of radio-labelled Ca2+ by jejunal biopsy specimens from control subjects, patients with idiopathic hypercalciuria and patients with renal stones without hypercalciuria, were compared. Radio-labelled Ca2+ uptake was investigated over the concentration range 0.1-5.0 mmol/l. For all subjects there was a linear relationship between Ca2+ uptake and medium concentration suggesting that Ca2+ uptake was a passive process. There was no significant difference in Ca2+ uptake between control subjects and patients with renal stones without hypercalciuria. Patients with idiopathic hypercalciuria, both absorptive and renal subtypes, showed increased Ca2+ uptake at all incubation medium concentrations. Assays of various biochemical parameters including alkaline phosphatase, Ca2+-activated ATPase, cyclic AMP and Ca2+-binding protein, in jejunal biopsy specimens showed no significant differences between control subjects and patients with idiopathic hypercalciuria. The results suggest that the intestinal abnormality in idiopathic hypercalciuria is due to enhanced permeability of the brush border membrane to Ca2+, possibly mediated by alterations in membrane lipids.
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PMID:Studies on intestinal calcium absorption in patients with idiopathic hypercalciuria. 654 1

Because calcium has been reported to modify gentamicin binding to its proximal tubular brush border membrane receptor, we studied the effects of dietary calcium loading and subsequent hypercalciuria on experimental gentamicin nephrotoxicity. Male Fischer 344 rats were fed one of two diets that were identical except for calcium carbonate content: normal (0.5%) and high (4%). The high-calcium diet made rats hypercalciuric but there were no differences between the two groups in inulin clearance, sodium or osmolar excretion, or serum calcium prior to gentamicin administration. Animals on both diets were treated with gentamicin, 20 mg/kg b.i.d., for periods of 3 to 21 days. Both groups developed acute renal failure, but animals on the high-calcium diet had less severe acute toxic injury, as evidenced by studies of inulin clearance, renal histology, and in vitro cortical uptake of NMN and PAH. Furthermore, calcium-loaded animals tended to have lower peak renal cortical gentamicin levels during the period of acute toxicity. The mechanism by which increased dietary calcium protects against gentamicin nephrotoxicity remains speculative. Calcium and gentamicin may compete for the same brush border receptor or alternatively parathyroid suppression may result in diminution in tubular cell membrane drug binding sites. The possibility that high-calcium diets exert a nonspecific salutory effect on proximal tubular cell integrity has not been excluded.
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PMID:Increasing dietary calcium moderates experimental gentamicin nephrotoxicity. 669 Jun 34

Vitamin D dependency is classified into two clinical disorders which are caused by genetic defect of vitamin D metabolism. Vitamin D dependent rickets type I and type II are the deficiency of 25-hydroxyvitamin D-1 alpha-hydroxylase and the defect of receptor for 1 alpha,25-dihydroxyvitamin D, respectively. In contrast, vitamin D resistance shows hypophosphatemia derived from disorder(s) of phosphate transport system in renal brush border membrane. There are three clinical entities such as hereditary hypophosphatemic rickets with hypercalciuria, familial hypophosphatemic rickets and oncogenic hypophosphatemic osteomalacia. However, the real pathogenesis of these disorders have not well been understood at present.
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PMID:[Vitamin D dependency and vitamin D resistance]. 838 22

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

Dent's disease is an 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 distributed in cells lining the proximal tubule (PT) of the kidney, where it co-localizes with albumin-containing endocytic vesicles that form part of the receptor-mediated endocytic pathway that mediates the reabsorption of low-molecular-weight (LMW) proteins filtered at the glomerular level. 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. Investigations conducted in a CLC-5 knockout (KO) mouse model harbouring all the characteristic renal tubular defects of Dent's disease showed a severe impairment of endocytosis by PT cells, such that the endocytic tracer peroxidase was poorly transferred into early endocytic vesicles. These data demonstrated that an impairment of receptor-mediated endocytosis in PT cells is the basis for the defective uptake of LMW proteins in patients with Dent's disease. The endocytosis and processing of LMW proteins involves the multiligand tandem receptors, megalin and cubilin, that are abundantly expressed at the brush border of PT cells. The characterization of the endocytic defect in CLC-5 KO mice revealed that ligands of both megalin and cubilin were affected, whereas a decrease in total kidney content of megalin and cubilin at the protein level was detected. 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 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 in important functions such as apical endocytosis, handling of proteins by renal tubular cells, calcium metabolism, and urinary acidification.
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PMID:Chloride channels and endocytosis: new insights from Dent's disease and CLC-5 knockout mice. 1561 95

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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PMID:Chloride channels and endocytosis: new insights from Dent's disease and ClC-5 knockout mice. 1563 24

Inorganic phosphate (Pi) is fundamental to cellular metabolism and skeletal mineralization. Ingested Pi is absorbed by the small intestine, deposited in bone, and filtered by the kidney where it is reabsorbed and excreted in amounts determined by the specific needs of the organism. Two distinct renal Na-dependent Pi transporters, type IIa (NPT2a, SLC34A1) and type IIc (NPT2c, SLC34A3), are expressed in brush border membrane of proximal tubular cells where the bulk of filtered Pi is reabsorbed. Both are regulated by dietary Pi intake and parathyroid hormone. Regulation is achieved by changes in transporter protein abundance in the brush border membrane and requires the interaction of the transporter with scaffolding and signaling proteins. The demonstration of hypophosphatemia secondary to decreased renal Pi reabsorption in mice homozygous for the disrupted type IIa gene underscores its crucial role in the maintenance of Pi homeostasis. Moreover, the recent identification of mutations in the type IIc gene in patients with hereditary hypophosphatemic rickets with hypercalciuria attests to the importance of this transporter in Pi conservation and subsequent skeletal mineralization. Two novel Pi regulating genes, PHEX and FGF23, play a role in the pathophysiology of inherited and acquired hypophosphatemic skeletal disorders and studies are underway to define their mechanism of action on renal Pi handling in health and disease.
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PMID:Phosphate transport: molecular basis, regulation and pathophysiology. 1727 Apr 30

Abnormalities of the inorganic phosphate (Pi) reabsorption in the kidney result in various metabolic disorders. Na+-dependent Pi (Na/Pi) transporters in the brush border membrane of proximal tubular cells mediate the rate-limiting step in the overall Pi-reabsorptive process. Type IIa and type IIc Na/Pi cotransporters are expressed in the apical membrane of proximal tubular cells and mediate Na/Pi cotransport; the extent of Pi reabsorption in the proximal tubules is determined largely by the abundance of the type IIa Na/Pi cotransporter. However, several studies suggest that the type IIc cotransporter in Pi reabsorption may also play a role in this process. For example, mutation of the type IIc Na/Pi cotransporter gene results in hereditary hypophosphatemic rickets with hypercalciuria, suggesting that the type IIc transporter plays an important role in renal Pi reabsorption in humans and may be a key determinant of the plasma Pi concentration. The type IIc Na/Pi transporter is regulated by parathyroid hormone, dietary Pi, and fibroblast growth factor 23, and studies suggest a differential regulation of the IIa and IIc transporters. Indeed, differences in temporal and/or spatial expression of the type IIa and type IIc Na/Pi transporters may be required for normal phosphate homeostasis and bone development. This review will briefly summarize the regulation of renal Pi transporters in various Pi-wasting disorders and highlight the role of a relatively new member of the Na/Pi cotransporter family: the type IIc Na/Pi transporter/SLC34A3.
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PMID:New aspect of renal phosphate reabsorption: the type IIc sodium-dependent phosphate transporter. 1768 85

The rate-limiting step of dietary calcium absorption in the intestine requires the brush border calcium entry channel TRPV6. The TRPV6 gene was completely sequenced in 170 renal calcium stone patients. The frequency of an ancestral TRPV6 haplotype consisting of three non-synonymous polymorphisms (C157R, M378V, M681T) was significantly higher (P = 0.039) in calcium stone formers (8.4%; derived = 502, ancestral = 46) compared to non-stone-forming individuals (5.4%; derived = 645, ancestral = 37). Mineral metabolism was investigated on four different calcium regimens: (i) free-choice diet, (ii) low calcium diet, (iii) fasting and (iv) after a 1 g oral calcium load. When patients homozygous for the derived haplotype were compared with heterozygous patients, no differences were found with respect to the plasma concentrations of 1,25-vitamin D, PTH and calcium, and the urinary excretion of calcium. In one stone-forming patient, the ancestral haplotype was found to be homozygous. This patient had absorptive hypercalciuria. We therefore expressed the ancestral protein (157R+378V+681T) in Xenopus oocytes and found a significantly enhanced calcium permeability when tested by a (45)Ca(2+) uptake assay (7.11 +/- 1.93 versus 3.61 +/- 1.01 pmol/min/oocyte for ancestral versus derived haplotype, P < 0.01). These results suggest that the ancestral gain-of-function haplotype in TRPV6 plays a role in calcium stone formation in certain forms of absorptive hypercalciuria.
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PMID:Gain-of-function haplotype in the epithelial calcium channel TRPV6 is a risk factor for renal calcium stone formation. 1827 10


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