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)

Active absorption of calcium from the intestine and reabsorption of calcium from the kidney are major determinants of whole body calcium homeostasis. Two recently cloned proteins, CaT1 and ECaC, have been postulated to mediate apical calcium uptake by rat intestine and rabbit kidney, respectively. By screening a rat kidney cortex library with a CaT1 probe, we isolated a cDNA encoding a protein (CaT2) with 84.2 and 73.4% amino acid identities to ECaC and CaT1, respectively. Unlike ECaC, CaT2 is kidney-specific in the rat and was not detected in intestine, brain, adrenal gland, heart, skeletal muscle, liver, lung, spleen, thymus, and testis by Northern analysis or reverse transcription polymerase chain reaction. The expression pattern of CaT2 in kidney was similar to that of calbindin D(28K) and the sodium calcium exchanger 1, NCX1, by in situ hybridization of adjacent sections. Furthermore, the mRNAs for CaT2 and calbindin D(28K) were colocalized in the same cells. CaT2 mediated saturable calcium uptake with a Michaelis constant (K(m)) of 0.66 mm when expressed in Xenopus laevis oocytes. Under voltage clamp condition, CaT2 promoted inward currents in X. laevis oocytes upon external application of Ca(2+). Sr(2+) and Ba(2+) but not Mg(2+) also evoked inward currents in CaT2-expressing oocytes. Similar to the alkaline earth metal ions, application of Cd(2+) elicited inward current in CaT2-expressing oocytes with a K(m) of 1.3 mm. Cd(2+), however, also potently inhibited CaT2-mediated Ca(2+) uptake with an IC(50) of 5.4 micrometer. Ca(2+) evoked currents were reduced at low pH and increased at high pH and were only slightly affected by the L-type voltage-dependent calcium channel antagonists, nifedipine, verapamil, diltiazem, and the agonist, Bay K 8644, even at relatively high concentrations. In conclusion, CaT2 may participate in calcium entry into the cells of the distal convoluted tubule and connecting segment of the nephron, where active reabsorption of calcium takes place via the transcellular route. The high sensitivity of CaT2 to Cd(2+) also provides a potential explanation for Cd(2+)-induced hypercalciuria and resultant renal stone formation.
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PMID:A rat kidney-specific calcium transporter in the distal nephron. 1087 38

The expression of calcium epithelium TRPV5, alcium binding protein Calbindin-D28k and Na(+)/Ca(2+) exchanger NCX1 was detected in renal distal convoluted tubule, and their effects on urine calcium reabsorption and the possible pathogenic mechanism in idiopathic hypercalciuria (IH) were investigated. Genetic hypercalciuric stone-forming (GHS) rats were chosen as animal models to study urine calcium reabsorption and IH. The cognate female and male rats that had maximal urine calcium were matched to breed next generation. Twelve GHS rats and 12 normal control (NC) SD rats were selected. Western blot and real time quantitative PCR were used to detect the protein and gene expression of TRPV5, Calbindin-D28k and NCX1 respectively. The expression levels of TRPV5 protein and mRNA in GHS rats were significantly lower than in NC rats (P<0.05). Western blot revealed that the expression levels of Calbindin-D28k in GHS rats and NC rats were 0.49+/-0.02 and 0.20+/-0.01 respectively, with the difference being significant between them (P<0.05). By using real time quantitative PCR, it was found that there was no significant difference in Calbindin-28k mRNA expression levels between GHS rats and NC rats (P>0.05). There was no significant difference in the NCX1 expression between GHS rats and NC rats (P>0.05). It was suggested that TRPV5 and Calbindin-D28k might play an important role in urine calcium reabsorption and IH, but they differently contributed to the pathogenesis: The down-regulation of TRPV5 decreases urine calcium reabsorption, directly leading to loss of the urine calcium and resulting in hypercalciuria, and the increased Calbindin-D28k expression could relieve, neutralize and decrease intracellular Ca(2+) concentration to maintain calcium balance. NCX1 is not the key protein in urine calcium reabsorption.
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PMID:The expression and implication of TRPV5, Calbindin-D28k and NCX1 in idiopathic hypercalciuria. 1884 43

Calcium homeostasis is altered in hypertensive patients. Indeed several investigators have reported that sodium-sensitive hypertension is associated with hypercalciuria. On the other hand, an independent clinical association exists between the occurrence of urolithiasis and hypertension, but the molecular mechanism(s) involved in stone formation by high blood pressure have not been so far clarified. To understand this association, it is obvious that we should analyze the effect of hypertension on the transport proteins involved in the renal calcium handling. In the kidney, the tubular reabsorption of calcium may proceed through transcellular and paracellular routes. At variance with the proximal tubule, along the distal segment, calcium transport is entirely sodium independent and occurs via the transcellular pathway. In particular, transcellular calcium reabsorption proceeds through a well-controlled sequence of events consisting of luminal calcium entry via the epithelial calcium channel (TRPV5), cytosolic diffusion of calcium bound to calbindin-D28K, and basolateral extrusion of calcium through the Na/Ca exchanger (NCX1) and plasma membrane Ca-ATPase (PMCA). It is highly likely that these proteins may be altered in hypertensive disease thus justifying and explaining the reported hypercalciuria. Experiments in hypertensive strains of animals exhibiting hypercalciuria may help to solve this puzzle.
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PMID:Hypertension and renal calcium transport. 2117 Aug 67

We developed a mathematical model of Ca(2+) transport along the late distal convoluted tubule (DCT2) and the connecting tubule (CNT) to investigate the mechanisms that regulate Ca(2+) reabsorption in the DCT2-CNT. The model accounts for apical Ca(2+) influx across transient receptor potential vanilloid 5 (TRPV5) channels and basolateral Ca(2+) efflux via plasma membrane Ca(2+)-ATPase pumps and type 1 Na(+)/Ca(2+) exchangers (NCX1). Model simulations reproduce experimentally observed variations in Ca(2+) uptake as a function of extracellular pH, Na(+), and Mg(2+) concentration. Our results indicate that amiloride enhances Ca(2+) reabsorption in the DCT2-CNT predominantly by increasing the driving force across NCX1, thereby stimulating Ca(2+) efflux. They also suggest that because aldosterone upregulates both apical and basolateral Na(+) transport pathways, it has a lesser impact on Ca(2+) reabsorption than amiloride. Conversely, the model predicts that full NCX1 inhibition and parathyroidectomy each augment the Ca(2+) load delivered to the collecting duct severalfold. In addition, our results suggest that regulation of TRPV5 activity by luminal pH has a small impact, per se, on transepithelial Ca(2+) fluxes; the reduction in Ca(2+) reabsorption induced by metabolic acidosis likely stems from decreases in TRPV5 expression. In contrast, elevations in luminal Ca(2+) are predicted to significantly decrease TRPV5 activity via the Ca(2+)-sensing receptor. Nevertheless, following the administration of furosemide, the calcium-sensing receptor-mediated increase in Ca(2+) reabsorption in the DCT2-CNT is calculated to be insufficient to prevent hypercalciuria. Altogether, our model predicts complex interactions between calcium and sodium reabsorption in the DCT2-CNT.
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PMID:Calcium reabsorption in the distal tubule: regulation by sodium, pH, and flow. 2315 95

The Na(+)/Ca(2+) exchanger (NCX) is a bidirectional transporter that is controlled by membrane potential and transmembrane gradients of Na(+) and Ca(2+). Although two isoforms of NCX1 and NCX2 are coexpressed on the basolateral membrane of the distal nephron, the functional significance of these isoforms is not entirely clear. Therefore, we used NCX1- and NCX2-heterozygote knockout mice (KO) and their double KO, as well as isoform-selective NCX inhibitors, to determine the roles of NCX isoforms in urine formation and electrolyte excretion in mice. NCX inhibitors, particularly NCX2-sensitive inhibitors, caused a dose-dependent natriuresis and in a higher dose, moreover, hypercalciuria. Consistently, NCX1-KO possessed normal renal function similar to wild-type mice (WT), whereas NCX2-KO and double KO exhibited moderate natriuresis and hypercalciuria. Notably, renal responses to YM-244769 were equivalently observed in NCX1-KO and WT, but disappeared in NCX2-KO and double KO. Thus, functional inhibition of NCX2 initially causes natriuresis, and further inhibition of NCX2 produces hypercalciuria, suggesting that the functional significance of NCX2 lies in Na(+) and Ca(2+) reabsorption of the kidney.
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PMID:Genetic knockout and pharmacologic inhibition of NCX2 cause natriuresis and hypercalciuria. 2549 2