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Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate how hypercalcemia blunts renal concentrating ability, alterations in basal and arginine vasopressin (AVP)-elicited osmotic water (Pf) and urea (Purea) permeabilities were measured in isolated perfused terminal inner medullary collecting ducts (IMCD) from control and chronically hypercalcemic rats after dihydrotachysterol (DHT) (M. Levi, L. Peterson, and T. Berl. Kidney Int. 23: 489-497, 1983) treatment. The IMCD Pf of DHT-treated rats did not increase significantly after AVP and was accompanied by a significant 87 +/- 4% reduction in aquaporin-2 (AQP-2) protein but not mRNA. In contrast, both basal and AVP-elicited IMCD Purea from DHT rats were significantly increased and accompanied by a significant 41 +/- 11% increase in AVP-regulated urea transporter protein content. Immunoblotting with anti-calcium/polyvalent cation-sensing receptor protein (CaR) antiserum revealed specific alterations in CaR bands in endosomes purified from the apical membranes of inner medulla of DHT rats. These data are the first detailed analyses of hypercalcemia-induced alterations in AVP-regulated permeabilities and membrane transporters in IMCD. We conclude that selective alterations in IMCD transport occur in hypercalcemia, permitting the body to dispose of excess calcium without forming calcium-containing renal stones.
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PMID:Vasopressin-elicited water and urea permeabilities are altered in IMCD in hypercalcemic rats. 961 37

The ability of parathyroid cells to recognize and respond to (i.e., "sense") small changes in the extracellular Ca2+ concentration (Ca2+o) plays a crucial role in mineral ion homeostasis. Expression cloning in Xenopus laevis oocytes enabled isolation of a cDNA coding for the bovine parathyroid CaR. CaRs were later isolated from human parathyroid and kidney, rat kidney, brain and C-cell, rabbit kidney, and chicken parathyroid. All are tissue and species homologs of the same ancestral gene. The predicted CaR protein has a large extracellular amino-terminus, which binds polycationic CaR agonists; a central core with seven membrane-spanning helices, documenting that it is a G protein-coupled receptor; and an approximately 200 amino acid carboxyl-terminal tail. The CaR is highly expressed in parathyroid and C-cells, along almost the entire nephron and gastrointestinal (GI) tract and within numerous regions of the brain, particularly hippocampus, cerebellum, and hypothalamus. The CaR's physiological importance has been documented by the identification of hyper- and hypocalcemic syndromes due to inactivating or activating CaR mutations, respectively. Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) are caused by loss-of-function CaR mutations producing Ca2+o "resistance," while autosomal dominant hypocalcemia is the result of activating mutations rendering CaRs overly sensitive to Ca2+o. In addition to showing altered parathyroid responsiveness to Ca2+o, patients with FHH reabsorb too much urinary Ca2+ and Mg2+ at a given Ca2+o, while those with autosomal dominant hypocalcemia excrete too much, illustrating the CaR's key role in renal handling of divalent cations. Recent in vitro data suggest that the CaR directly regulates renal water handling in the collecting duct. Indeed, patients with FHH concentrate their urine normally, despite their hypercalcemia, while those with autosomal dominant hypocalcemia can exhibit impaired urinary concentration at normal or even low Ca2+o, suggesting that the CaR enables coordination of renal calcium and water handling. In addition to serving these "homeostatic" roles, the CaR likely also enables Ca2+o to serve additional roles as an extracellular messenger. The receptor regulates key Ca2+ and K(+)-permeable ion channels in hippocampal and other brain cells and likely senses local changes in Ca2+o within the brain microenvironment accompanying neuronal activation. It is also present in and regulates ion channels in lens epithelial cells, potentially playing some role in cataract development in hypoparathyroid patients. In keratinocytes and epithelial cells of the gastrointestinal tract, in contrast, the CaR may regulate cellular proliferation and differentiation, processes known to be modulated by Ca2+o in these cell types. Thus, in addition to sensing and regulating systemic Ca2+o, the CaR likely enables Ca2+o to act as a local signal for cells within specific microenvironments, such as the brain or eye.
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PMID:The calcium-sensing receptor (CaR) permits Ca2+ to function as a versatile extracellular first messenger. 976 11

Hypercalcemia is frequently associated with a urinary concentrating defect and overt polyuria. The molecular mechanisms underlying this defect are poorly understood. Dysregulation of aquaporin-2 (AQP2), the predominant vasopressin-regulated water channel, is known to be associated with a range of congenital and acquired water balance disorders including nephrogenic diabetes insipidus and states of water retention. This study examines the effect of hypercalcemia on the expression of AQP2 in rat kidney. Rats were treated orally for 7 d with dihydrotachysterol, which produced significant hypercalcemia with a 15 +/- 2% increase in plasma calcium concentration. Immunoblotting and densitometry of membrane fractions revealed a significant decrease in AQP2 expression in kidney inner medulla of hypercalcemic rats to 45.7 +/- 6.8% (n = 11) of control levels (100 +/- 12%, n = 9). A similar reduction in AQP2 expression was seen in cortex (36.9 +/- 4.2% of control levels, n = 6). Urine production increased in parallel, from 11.3 +/- 1.4 to a maximum of 25.3 +/- 1.9 ml/d (P < 0.01), whereas urine osmolality decreased from 2007 +/- 186 mosmol/kg x H2O to 925 +/- 103 mosmol/kg x H2O (P < 0.01). Immunocytochemistry confirmed a decrease in total AQP2 labeling of collecting duct principal cells from kidneys of hypercalcemic rats, and reduced apical labeling. Immunoelectron microscopy demonstrated a significant reduction in AQP2 labeling of the apical plasma membrane, consistent with the development of polyuria. In summary, the results strongly suggest that AQP2 downregulation and reduced apical plasma membrane delivery of AQP2 play important roles in the development of polyuria in association with hypercalcemia.
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PMID:Decreased aquaporin-2 expression and apical plasma membrane delivery in kidney collecting ducts of polyuric hypercalcemic rats. 984 72

Infusing urea into low-protein-fed mammals increases urine concentration within 5-10 min. To determine which urea transporter may be responsible, we measured urea transport in perfused IMCD3 segments [inner medullary collecting duct (IMCD) segments from the deepest third of the IMCD] from low-protein-fed rats. Basal facilitated urea permeability increased 78%, whereas active urea secretion was completely inhibited. This suggests that upregulation of facilitated urea transport may mediate the rapid increase in urine concentration. Next, expression of active urea transporter(s) in perfused IMCDs was determined in rats with other causes of reduced urine concentrating ability. In untreated and water diuretic rats, IMCD1 segments showed no active urea transport, nor did IMCD2 segments from untreated or hypercalcemic rats. In IMCD1 segments from hypercalcemic rats, active urea reabsorption was induced. The induced active urea reabsorption was completely inhibited by replacing perfusate Na+ with N-methyl-D-glucamine (NMDG+). Active urea secretion was completely inhibited in IMCD3 segments from hypercalcemic rats. In contrast, water diuresis stimulated active urea secretion in IMCD2 segments. The induced active urea secretion was inhibited by phloretin, ouabain, triamterene, or replacing perfusate Na+ with NMDG+. In conclusion, the response of active urea transporters to reductions in urine concentrating ability follows two paradigms: one occurs with hypercalcemia or a low-protein diet, and the second occurs only in water diuresis.
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PMID:Urea transport processes are induced in rat IMCD subsegments when urine concentrating ability is reduced. 988 81

The cloning of a G protein-coupled, extracellular calcium-sensing receptor (CaSR) provided direct evidence that Ca(2+)-sensing can occur through receptor-mediated activation of G proteins and their associated downstream regulators of cellular function. CaSR transcripts and protein are present in various tissues that are involved in Ca2+ homeostasis and that do not have well-established roles in Ca balance as well. The physiological relevance of the CaSR has been established by identifying inherited hyper-and hypocalcemia disorders resulting from CaSR mutations: familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism result from inactivating CaSR mutations while autosomal dominant hypocalcemia is caused by activating mutations. CaSR may also play a role in water metabolism. Calcimimetics that activate CaSR are undergoing clinical trials and might prove effective in manipulation of serum calcium concentration and urinary calcium excretion through CaSR activities.
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PMID:[Calcium-sensing receptor and its related diseases]. 1019 62

Polydextrose (CAS no. 68424-04-4) is a water-soluble polymer of glucose that provides to foods the bulk and texture of sucrose. There are two main forms of polydextrose, an acidic form (PD-A) and a neutralized potassium salt (PD-N). Polydextrose is resistant to mammalian metabolic and microbial degeneration, rendering it both low in caloric value and non-cariogenic. Little polydextrose is absorbed intact although some is metabolized by caecal/colonic bacteria. At high enough levels of ingestion, this bacterial metabolism results in flatus, bloating, loose stools and ultimately a frank diarrhoea. Microbial metabolism also produces some volatile fatty acids that are absorbed by the animal and have calorigenic value. The species and dose threshold for persistent loose stools/watery diarrhoea determines the degree of electrolyte loss by the animal. In the dog, an obligate carnivore, sodium-sparing activity by the kidney and concomitant and obligatory calcium reuptake result in a well-defined aetiology of hypercalcaemia and subsequent nephrocalcinosis, particularly for PD-N. Of the species tested, the dog was the most sensitive to this carbohydrate with a no-effect level of 2000 mg/kg body weight/day. Omnivores, including the rat, mouse and monkey, have a no-effect level ranging from 2500 to 10,000 mg/kg body weight/day. No toxicity has been demonstrated in man, although the dose for laxation (to be distinguished from diarrhoea) is approximately 90 g/day (v. sorbitol at 70 g/day). Polydextrose did not show any reproductive toxicity, teratology, carcinogenesis, mutagenicity or genotoxicity. Polydextrose has been approved for food additive use (21 CFR 172.841) in the US, and an "ADI not specified" by the Joint WHO/FAO Expert Committee on Food Additives (JECFA, 1987). It has been approved in over 50 countries around the world and has been used extensively in the diet for over15 years. Specification monographs are published in the Food Chemicals Codex (FCC) (NAS, 1996) and the FAO Compendium (JECFA, 1995). This review provides an overview of the studies and salient data, not previously reported in the scientific literature, which had been submitted to regulatory agencies in support of these approvals.
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PMID:A review of the studies of the safety of polydextrose in food. 1022 45

The synergism/antagonism between interleukin (IL)-1beta and parathyroid hormone (PTH) has been the subject of in vitro and in vivo work, but a possible direct action of the cytokine on PTH release has not been reported. We have investigated the effect of a continuous infusion of human recombinant IL-1beta (rIL-1beta) on circulating PTH during a 14-day period in 7-week-old female rats. This time interval was chosen in order to exclude initial hypercalcemia and to enable data collection under steady-state conditions. Five groups of 20 animals each had miniosmotic pumps (Alzet 2002, 200 microl) implanted subcutaneously and primed to release either distilled water (controls) or 100, 500, 1,000 and 2, 000 ng/24 h of rIL-1beta. Blood was drawn on days 1 and 14 for PTH, corticosterone and Ca2+ determinations. Adequate biological activity of the infused rIL-1beta was supported by elevated rectal temperature records and significant elevations of plasma corticosterone on day 14. The 100-ng dose had no effect but 500-2, 000 ng rIL-1beta/24 h significantly reduced plasma PTH in a dose-dependent manner down to 54% of basal value (20.4 +/- 1.1 vs. 15.3 +/- 1.4 pg/ml for 500 ng, p < 0.005; 20.5 +/- 1.3 vs 12.3 +/- 1.1 for 1,000 ng, p < 0.001, and 19.5 +/- 2.0 vs. 10.6 +/- 1.1 pg/ml for 2,000 ng, p < 0.0008). Despite these findings, no differences in blood Ca2+ could be detected between treated animals and controls. The following conclusions can be inferred from the foregoing: Systemic administration of rIL-1beta to rats induced a dose-dependent fall in circulating PTH without altering calcemia, calling into question the biological relevance of the former finding. Although the recorded PTH depression may indeed not have been severe enough to cause hypocalcemia, it can be hypothesized that osteoclast activation by rIL-1beta would enhance bone mineral release into the pool compensating for depressed PTH activity.
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PMID:Long-term systemic administration of human recombinant interleukin-1beta induces a dose-dependent fall in circulating parathyroid hormone in rats. 1035 96

Baseline renal function data was collected during 24-hr periods of feeding and fasting from three male and three female adult Asian small-clawed otters (Aonyx cinerea) with calcium oxalate urolithiasis. Urine was analyzed for calcium, phosphorus, and oxalate, and urinalyses were performed. There was no evidence of glucosuria, which has been previously reported in Asian small-clawed otters with urolithiasis. Urinary oxalate levels were quite high when compared with those of dogs and humans without uroliths, and the ratio of urinary oxalate to calcium was close to 1:1 during periods of food consumption. There was no significant difference in urinary oxalate excretion between the fed and fasting states. Urinary calcium excretion was five times greater during feeding than during fasting. Calcium levels were higher in the otters than those reported for dogs without uroliths but were similar to those for normal humans. Water consumption and urine production were significantly higher during periods of food consumption. Serum chemistry analyses and electrolyte levels were also determined. There was no evidence of hypercalcemia. Fractional clearance of calcium and phosphorus and endogenous creatinine clearance were significantly higher during food consumption than during fasting. Parathyroid hormone levels were similar to those reported for dogs and cats. Serum 25-hydroxy-vitamin D was slightly lower in the otters than in dogs.
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PMID:Evaluation of urinary and serum metabolites in Asian small-clawed otters (Aonyx cinerea) with calcium oxalate urolithiasis. 1036 44

Recognizing the role of the extracellular calcium-sensing receptor (CaR) in mineral metabolism greatly improves our understanding of calcium homeostasis. The biology of the low affinity, G-protein-coupled CaR and the effects of its activation in various tissues are reviewed. Physiological roles include regulation of parathyroid hormone (PTH) secretion by small changes in ionized calcium (Ca2+) and control of urinary calcium excretion with small changes in blood Ca2+. The CaR also affects the renal handling of sodium, magnesium and water. Mutations affecting the CaR that make it either less or more sensitive to Ca2+ cause various clinical disorders; heterozygotes of mutations causing the CaR to be less sensitive to extracellular Ca2+ cause familial hypocalciuric hypercalcemia, while the homozygous form results in severe infantile hyperparathyroidism. Mutations causing increased sensitivity of the CaR to extracellular Ca2+ produce hereditary forms of hypoparathyroidism. Disorders, such as primary and secondary hyperparathyroidism, may exhibit acquired abnormalities of the CaR. Calcimimetic drugs, which amplify the sensitivity of the CaR to Ca2+, can suppress PTH levels, leading to a fall in blood Ca2+. Experiences with this agent in patients with secondary and primary hyperparathyroidism and parathyroid carcinoma are summarized. In animals and humans with hyperparathyroidism, this agent produces a dose-dependent fall in PTH and blood Ca2+, with larger doses causing more sustained effects. The treatment has been short-term except for one patient followed for more than 600 days for parathyroid carcinoma; nonetheless the drug did not cause major side-effects and appears to be safe. Further long-term controlled studies are needed with calcimimetic agents of this type.
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PMID:Calcium-sensing receptor and calcimimetic agents. 1063 65

Due to urea's role in producing concentrated urine, its transport is critically important to the conservation of body water. Within the renal inner medulla, urea is transported by both facilitated and active urea transport mechanisms. The vasopressin-regulated, facilitated urea transporter (UT-A1) in the terminal inner medullary collecting duct (IMCD) permits high rates of transepithelial urea transport and results in delivery of large quantities of urea into the deepest portions of the inner medulla where it is needed to maintain a high interstitial osmolality for maximal urine concentration. Four cDNA isoforms of the UT-A urea transporter family have been cloned. In addition, there are three secondary active, sodium-dependent, urea transport mechanisms in IMCD subsegments: (1) active urea secretion in the apical membrane of the terminal IMCD from untreated rats; (2) active urea absorption in the apical membrane of the initial IMCD from low-protein fed or hypercalcemic rats; and (3) active urea absorption in the basolateral membrane of the initial IMCD from furosemide-treated rats. This review will focus on integrative studies of the rapid and long-term regulation of urea transporters in rats with reduced urine concentrating ability. These studies led to the surprising result that the basal-facilitated urea permeability in the terminal IMCD and UT-A1 protein abundance are increased during in vivo conditions associated with an impaired urine concentrating ability. In contrast, there are two response patterns of active urea transporters: (1) hypercalcemia, a low-protein diet, and furosemide result in induction of active urea absorption in the initial IMCD, albeit by different mechanisms, and inhibition of active urea secretion in the terminal IMCD; while (2) water diuresis results in up-regulation of active urea secretion in the terminal IMCD without any active urea absorption in the initial IMCD. The first pattern contributes to the urine concentrating defect by increasing urea delivery to the base of the inner medulla, thus decreasing urea delivery distally to the inner medullary tip. The second response pattern will directly decrease urea content in the deep inner medulla. UT-A urea transporters are also expressed outside the kidney. Recent studies show that the liver has phloretin-inhibitable urea transport and that it occurs via a 49 kDa UT-A protein. When rats are made uremic, the abundance of this 49 kDa UT-A protein increases in the liver in vivo. This up-regulation of the 49 kDa UT-A protein may allow hepatocytes to increase ureagenesis to reduce the accumulation of ammonium and/or bicarbonate in uremia.
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PMID:Regulation of urea transporter proteins in kidney and liver. 1074 66


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