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

We recently cloned extracellular Ca(2+)-sensing receptors (CaRs) from bovine parathyroid and rat kidney that play key roles in Ca2+ homeostasis. Inactivating mutations of the CaR in the inherited human disorder, familial hypocalciuric hypercalcemia, cause reduced responsiveness of the parathyroid to extracellular Ca2+ (Cao2+), as well as abnormally avid renal tubular reabsorption of both Ca2+ and Mg2+ in the distal tubule, suggesting an important role for the CaR in regulating parathyroid hormone (PTH) secretion and renal handling of divalent cations. High Cao2+ also inhibits vasopressinstimulated adenosine 3',5'-cyclic monophosphate accumulation in the medullary thick ascending limb (MTAL) and water reabsorption in the collecting duct (CD) and modulates various other aspects of renal function. The relevance of the CaR to these processes, however, is uncertain. Reduced responsiveness of vasopressin-and PTH-mediated actions on the kidney have been described in the newborn that could potentially reflect effects of the CaR on these aspects of renal function. To define further the role of the CaR in regulating renal function, including the above-mentioned changes during the perinatal period, therefore, we have studied its ontogeny in rat kidney. Northern and Western blot analyses, as well as immunohistochemistry with CaR-specific probes, demonstrate that there is little prenatal expression of the extracellular Ca(2+)-sensing receptor, except in large tubules and branching ureteric buds of developing nephrons. Postnatally, CaR mRNA and protein increase markedly during the 1st wk, related principally to expression of the receptor in the developing TAL and, to a lesser extent, in the CD. The level of expression of the receptor remains nearly constant after postnatal day 14. These results demonstrate that the perinatal increases in expression of CaR mRNA and protein parallel its tissue-specific renal expression. Furthermore, it is possible that some of the previously described changes in renal handling of divalent cations and water in the perinatal and immediate postnatal period are related, in part, to the increasing levels of expression of the CaR and resultant inhibitory effects on the actions of PTH and antidiuretic hormone on the developing nephron.
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PMID:Ontogeny of the extracellular calcium-sensing receptor in rat kidney. 885 37

The recent cloning of a [Ca2+]o-sensing receptor from several different tissues in several species directly demonstrates that a variety of cells can directly recognize and respond to small changes in their ambient level of [Ca2+]o through a G protein-coupled, cell surface receptor. This finding directly documents that [Ca2+]o can act as an extracellular, first messenger in addition to subserving its better known role as an intracellular second messenger. Several of the tissues expressing the CaR are important elements in the calcium homeostatic system that have long been known to be capable of sensing [Ca2+]o, such as parathyroid and thyroidal C cells. The presence of the receptor in the kidney, however, provides strong evidence that several of the long-recognized but poorly understood direct actions of [Ca2+]o on renal function could be mediated by the CaR. These actions include the up-regulation of urinary calcium and magnesium excretion in the setting of hypercalcemia, which complements the indirect inhibition of renal tubular reabsorption of calcium that results from high [Ca2+]o-mediated inhibition for PTH secretion. The impaired renal concentrating capacity in hypercalcemia is likely a manifestation of a homeostatically important interaction between the regulation of renal calcium and water handling that reduces the risk of pathological deposition of calcium in the kidney when there is a need to dispose of excess, calcium in the urine. In this regard, the availability of human syndromes of [Ca2+]o "resistance" or "overresponsiveness" due to loss-of-function or gain-of-function mutations in the CaR, respectively, have provided useful experiments in nature that have clarified the importance of the receptor in both abnormal and normal physiology. Much remains to be learned, however, about the role of the CaR in locations, such as the brain, where it likely responds to local rather than systemic levels of [Ca2+]o. In such sites, it may represent an important modulator of neuronal function, responding to [Ca2+]o as a neuromodulator or even neurotransmitter. The development of therapeutics that either activate or inhibit the function of the CaR may be useful for treating a variety of conditions in which the receptor is either under- or overactive. Finally, it would not be surprising to discover additional receptors for [Ca2+]o or for other ions (the CaR may, in fact, be an important [Mg2+]o-sensor) that could function abnormally in certain disease states and be amenable to pharmacological manipulation with ion receptor-based therapeutics.
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PMID:The calcium-sensing receptor: a window into the physiology and pathophysiology of mineral ion metabolism. 885 47

Using a strategy based on homology to the bovine parathyroid Ca(2+)-sensing receptor previously identified by us (5), we have recently isolated an extracellular, G protein-coupled Ca2+/ polyvalent cation-sensing receptor, RaKCaR (22), from rat kidney. The localization and physiological role(s) of this receptor in the kidney are not well understood. In the present study, we assessed the distribution of mRNAs for RaKCaR and the parathyroid hormone/parathyroid hormone-related protein (PTH/PTHrP) receptor along the rat nephron by in situ hybridization and reverse transcriptase-polymerase chain reaction of microdissected nephron segments. Our results show that transcripts for both receptors coexpress at glomeruli, proximal convoluted tubule, proximal straight tubule, cortical thick ascending limb, distal convoluted tubule, and cortical collecting duct. In addition, RaKCaR (but not PTH/PTHrP receptor) transcripts were found in the medullary thick ascending limb and outer medullary and inner medullary collecting ducts. These findings raise the possibility of roles for RaKCaR not only in the regulation of divalent mineral reabsorption but also in water reabsorption and urinary concentration. Taken together, our results provide new insights in understanding the effects of hypercalcemia on hormone-stimulated salt and water transport.
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PMID:Localization of the extracellular Ca(2+)-sensing receptor and PTH/PTHrP receptor in rat kidney. 889 27

The relationship between PTH and calcium is best represented as a sigmoidal curve. In the normal animal and human, basal PTH is positioned at approximately 25% of maximal PTH and responds rapidly to small changes in calcium in either direction. Since PTH secretion is designed to respond to either hypo- or hypercalcemia, the study was performed to evaluate whether the parathyroid gland would respond differently to hypocalcemia when the reduction in serum calcium was initiated from sustained hypercalcemia with maximal PTH suppression. Nine dogs were studied and the experimental protocol consisted of two separate parts in which the same dogs were used and the order of study was randomly assigned. For the hypercalcemic part, calcium chloride was infused intravenously to increase serum calcium to between 1.60 and 1.70 mM at 30 minutes and then continued for another 90 minutes to clamp the serum calcium at this level. Sodium EDTA was then infused to lower the serum calcium at a constant rate to less than 0.85 mM. For the normocalcemic part, 5% dextrose in water was infused for two hours to control for fluid volume and time, and then EDTA was infused to lower the serum calcium at a constant rate to less than 0.85 mM. The results show that for the same serum calcium concentration at every 0.05 mM decrement in serum calcium below normal, PTH was less in the hypercalcemic than the normocalcemic dogs (P < 0.02). During the induction of hypocalcemia in the normocalcemic dogs, a characteristic sigmoidal curve was observed in which a small decrease in the serum calcium induced a brisk increase in PTH and a maximal PTH level was rapidly attained; however, during the induction of hypocalcemia in the hypercalcemic dogs, the increase in PTH was progressive, but linear and it was not certain that a maximal PTH level was attained. In conclusion, a sustained period of hypercalcemia resulted in a decreased PTH response to hypocalcemia and reduced the efficiency of the sigmoidal PTH-calcium relationship. Whether the mechanism for this difference in PTH secretion is due to secretory products, modification of the calcium receptor, or changes in intercellular communication among parathyroid cells deserves further study.
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PMID:A reduced PTH response to hypocalcemia after a short period of hypercalcemia: a study in dogs. 894 17

In experiment on rats functional overload (36 hours of water depression) helps in establishing the fact that the kidney subjected to the actions of non-specific factors of transplantation (ischemia, denervation, delymphatization) restores its ability to keep osmotic haemostasis to the 17th day. The same alterative factors against a background of hypercalcemia is not accompanied by the restoration of osmoconcentration functions to the 30th day of the experiment. One of the causes of this phenomenon may be the increase in the velocity of filtration in the kidney.
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PMID:[The osmolar concentrating function of the kidneys under the influence of nonspecific transplantation factors against a background of hypercalcemia]. 902 99

The divalent mineral cations Ca2+ and Mg2+ play many and diverse roles both in the function of cells and in extracellular processes. The metabolism of these cations is a complex process involving the coordinated function of several organ systems and endocrine glands. A recently cloned G-protein-coupled receptor responds to extracellular calcium concentration (Ca2+0-sensing receptor, CaSR) and mediates several of the known effects of Ca2+0 on parathyroid and renal function. The CaSR, which is also expressed in a number of other tissues including thyroidal C-cells, brain and gastrointestinal tract, may function as a Ca2+0 sensor in these tissues as well. Thus, Ca2+0 is a first messenger (or hormone) which, via CaSR-mediated activation of second messenger systems (e.g. phospholipases C and A2, cyclic AMP) leads to altered function of these cells. Several mutations in the human CaSR gene have been identified and shown to cause three inherited diseases of calcium homeostasis, clearly implicating the CaSR as an important component of the homeostatic mechanism for divalent mineral ions. Ca2+ and Mg2+ losses from the body are regulated by altering the urinary excretion of these divalent cations. The localization of the CaSR transcripts and protein in the kidney not only provides a basis for a direct Ca2+0 (or Mg2+0)-mediated regulation of Ca2+ (and Mg2+) excretion but also suggests a functional link between divalent mineral and water metabolism. In the kidney, the thick ascending limb of Henle (TAL) plays crucial roles in regulating both divalent mineral reabsorption and urine concentration. Recent studies have suggested models whereby extracellular Ca2+, via the CaSR expressed in the TAL as well as in the collecting duct system, modulates both Ca2+ 0 and Mg2+ 0 as well as water reabsorbtion. When taken together, these studies suggest that the CaSR not only provides the primary mechanism for Ca2+ 0-mediated regulation of parathyroid hormone secretion from parathyroid glands but also for direct modulation of renal divalent mineral excretion and urinary concentrating ability. These latter functions may furnish a mechanism for integrating and balancing water and divalent cation losses that minimizes the risk of urinary tract stone formation. This mechanism can explain hypercalcemia-mediated polyuria (diabetes insipidus).
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PMID:Role of the Ca(2+)-sensing receptor in divalent mineral ion homeostasis. 905 Feb 37

Rana pipiens were divided into four groups: controls; hypocalcemic frogs, depleted of salts by acclimation to deionized water; hypercalcemic frogs, calcium-loaded by the introduction of 40 mumol calcium gluconate; and frogs exposed to the potential competing ions Mg2+, Sr2+, and Ba2+. All groups displayed calcium influx that was proportional to external [Ca2+]; however, the group acclimated to deionized water also displayed hypocalcemia (P < 0.025) and enhanced Ca2+ influx at higher (> 0.3 mM) external [Ca2+]. Ca2+ efflux was depressed in hypocalcemic frogs, and thus net Ca2+ flux shifted from net loss in control frogs to net uptake in hypocalcemic frogs. Hypocalcemia also resulted in increased skin Ca2+ deposits which may be related to a decreased Ca2+ (and other ions) permeability as a consequence of the acclimation to deionized water. Another group of frogs was Ca(2+)-loaded by injecting calcium gluconate: Sodium gluconate controls did not significantly alter Ca2+ fluxes. The frogs that received calcium gluconate treatments became hypercalcemic (P < 0.01) and did not display significant changes in calcium fluxes, nor did they show significant changes in skin calcium deposits. We conclude that hypocalcemia leads to regulatory responses that stimulate active Ca2+ transport in Rana pipiens skin and possibly inhibits cutaneous and renal efflux. We also conclude that hypercalcemia does not alter calcium fluxes across skin. The ions from Group IIA of the Periodic Table of Elements had little effect on Ca2+ fluxes at concentrations ranging from 0.5-4.0 mM; neither Sr2+ or Ba2+ affected Ca2+ influx. The only divalent ion tested that influenced Ca2+ was Mg2+, which significantly inhibited Ca2+ influx but only at 4.0 mM or eight times the external [Ca2+]. We conclude, therefore, that the Ca2+ transport mechanism is fairly specific for Ca2+ within Group IIA.
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PMID:Cutaneous transport of Ca2+ in the frog Rana pipiens: significance and specificity. 912 56

The alteration in calcium metabolism in rats ingested with saline was investigated. Rats were freely given saline as drinking water for 2 and 7 days. Calcium concentration in the serum was significantly elevated by saline ingestion for 2 and 7 days, while serum inorganic phosphorus concentration was not altered. Serum urea nitrogen concentration was significantly increased by saline ingestion for 7 days. Calcium content in the femoral-diaphyseal and metaphyseal tissues was not altered by saline ingestion for 7 days. Calcium content in the kidney cortex was significantly elevated by saline ingestion for 7 days. Ca2+-ATPase activity in the basolsateral membranes of kidney cortex was clearly increased by saline ingestion for 2 and 7 days. The enzyme activity was not altered by the addition of sodium chloride (10(-3) and 10(-2) M), parathyroid hormone (10(-7) and 10(-6) M), and calcitonin (3 x 10(-8) and 3 x 10(-7) M) in the enzyme reaction mixture. A calcium-binding protein regucalcin mRNA expression in the kidney cortex was markedly suppressed by saline ingestion for 7 days, although such a suppression was not seen for 2 days. These results suggest that saline ingestion causes the disturbance of calcium transport system in the kidney cortex of rats, and that the renal disorder may induce hypercalcemia.
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PMID:Alterations in Ca2+-ATPase activity and calcium-binding protein regucalcin mRNA expression in the kidney cortex of rats with saline ingestion. 914 14

Specialized cells (i.e., parathyroid chief cells) that sense changes in the extracellular calcium concentration are a key element in mineral ion homeostasis. The Ca2+o-sensing receptor (CaR) originally cloned from bovine parathyroid is also present in multiple nephron segments involved in Ca2+o homeostasis as well as in other sites that are not, such as brain, lung, large and small intestine. The physiological relevance of the CaR has been established by identifying hyper- and hypocalcemic disorders resulting from CaR mutations: familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism result from inactivating CaR mutations, while an autosomal dominant form ofhypocalcemia is caused by activating mutations. In addition to sensing Ca2+o and Mg2+o abnormally (the latter suggesting the CaR acts as an Mg2+o-sensing receptor), persons with FHH have alterations in their handling of water, supporting a role for the CaR in integrating mineral ion and water metabolism. Drugs that activate the CaR ('calcimimetics') are currently undergoing clinical trials and will permit pharmacological manipulation of the receptor when it functions abnormally (e.g., in primary hyperparathyroidism).
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PMID:Mutations in the calcium-sensing receptor and their clinical implications. 936 89

Many papers have reported that chronic hypercalcemia induced either by large doses of vitamin D or by the administration of calcium or parathormone, produces hypertrophy and hyperplasia of C cells. However, more recent studies suggest that the effect of elevated calcium or 1.25(OH)2D3 concentration on the production of calcitonin may be more complex than previously suspected. To assess the validity of such a response an experimental model, where hypercalcemia was induced with vitamin D3 overdose, was designed. Male Wistar rats were administered vitamin D3 chronically (50,000 IU per 100 ml of drinking water with or without CaCl2). Serum calcium and calcitonin levels were determined. C cells were stained by immunohistochemistry using calcitonin and neuronal specific enolase (NSE) antibodies and their percentage was calculated by a morphometric analysis. We also investigated the ultrastructural characteristic of the C cells under experimental conditions. C cells did not have a proliferative response rather a decrease in their number was observed after 1 month of treatment with 25,000 IU of vitamin D3 (1.55 vs 2.43% in control animals) and 3 months with vitamin plus CaCl2 (2.27% vs 3.62% in control animals). In addition, no significant changes in serum calcitonin levels were observed during the experimental period. We conclude that rat C cells do not respond with hypertrophic and hyperplastic changes in a hypercalcemic state due to an intoxication with vitamin D3.
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PMID:Chronic hypervitaminosis D3 determines a decrease in C-cell numbers and calcitonin levels in rats. 958 84


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