The calcium-sensing receptor (CaSR) defends against hypercalcemia independently of its regulation of parathyroid hormone secretion

Kantham, Lakshmi; Quinn, Steven; Egbuna, Ogo; Baxi, Khanjan; Butters, Robert R.; Pang, Jian; Pollak, Martin R.; Goltzman, David; Brown, Edward M.

doi:10.1152/ajpendo.00315.2009

Cited by 131 publications

(118 citation statements)

References 50 publications

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“…Nevertheless, PTH seemed to set a floor level defending against hypocalcemia, mindful that KO of claudin-14 could not correct the hypocalcemia induced by cinacalcet. This phenomenon has also been observed in the work by Kantham et al, 40 which showed that the presence of CaSR in the setting of PTH KO could not rescue the CaSR/PTH double KO from hypocalcemia.…”

Section: Discussionsupporting

confidence: 71%

“…An important finding from these mice was the clear demonstration that suppression of PTH was not required for robust defense against various hypercalcemic challenges. 40 40 A direct support for the renal role of CaSR in defending hypercalcemia was provided by Toka et al 41 With a kidney-specific CaSR KO mouse model, Toka et al 41 have elegantly shown that the KO mice excrete significantly less Ca ++ in face of hypercalcemia, although their PTH secretion was intact. Loupy et al 14 have studied the renal role of CaSR in cases of hypercalcemia induced by the calcilytic compound NPS2143.…”

Section: Discussionmentioning

confidence: 99%

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Claudin-14 Underlies Ca++-Sensing Receptor–Mediated Ca++ Metabolism via NFAT-microRNA–Based Mechanisms

Gong

Hou

2014

Journal of the American Society of Nephrology

109

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Pathologic dysregulation of extracellular calcium metabolism is difficult to correct. The extracellular Ca ++ -sensing receptor (CaSR), a G protein-coupled receptor that regulates renal Ca ++ handling through changes in paracellular channel permeability in the thick ascending limb, has emerged as an effective pharmacological candidate for managing calcium metabolism. However, manipulation of CaSR at the systemic level causes promiscuous effects in the parathyroid glands, kidneys, and other tissues, and the mechanisms by which CaSR regulates paracellular transport in the kidney remain unknown. Here, we describe a CaSR-NFATc1-microRNAclaudin-14 signaling pathway in the kidney that underlies paracellular Ca ++ reabsorption through the tight junction. With CaSR-specific pharmacological reagents, we show that the in vivo gene expression of claudin-14 is regulated through a transcriptional mechanism mediated by NFATc1-microRNA and associated chromatin remodeling. Transgenic knockout and overexpression approaches showed that claudin-14 is required for CaSR-regulated renal Ca ++ metabolism. Together, our results define an important signaling cascade that, when dysregulated, may mediate Ca ++ imbalance through changes in tight junction permeability.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Claudin-14 Underlies Ca++-Sensing Receptor–Mediated Ca++ Metabolism via NFAT-microRNA–Based Mechanisms

Gong

Hou

2014

Journal of the American Society of Nephrology

109

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“…Data from these models suggest that the extraparathyroid CaSR may limit the variability of blood and urine Ca (8). Moreover, studies in mice have shown that the CaSR in kidney and/or C cells plays an important homeostatic role in the defense against hypercalcemia induced by oral Ca overload or by PTH or calcitriol administration (9,10). However, these experiments did not aim at providing evidence that extraparathyroid CaSR plays a significant role as a direct determinant of blood Ca concentration.…”

Section: Introductionmentioning

confidence: 99%

PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor

Loupy¹,

Ramakrishnan²,

Wootla³

et al. 2012

J. Clin. Invest.

181

171

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Tight regulation of calcium levels is required for many critical biological functions. The Ca 2+ -sensing receptor (CaSR) expressed by parathyroid cells controls blood calcium concentration by regulating parathyroid hormone (PTH) secretion. However, CaSR is also expressed in other organs, such as the kidney, but the importance of extraparathyroid CaSR in calcium metabolism remains unknown. Here, we investigated the role of extraparathyroid CaSR using thyroparathyroidectomized, PTH-supplemented rats. Chronic inhibition of CaSR selectively increased renal tubular calcium absorption and blood calcium concentration independent of PTH secretion change and without altering intestinal calcium absorption. CaSR inhibition increased blood calcium concentration in animals pretreated with a bisphosphonate, indicating that the increase did not result from release of bone calcium. Kidney CaSR was expressed primarily in the thick ascending limb of the loop of Henle (TAL). As measured by in vitro microperfusion of cortical TAL, CaSR inhibitors increased calcium reabsorption and paracellular pathway permeability but did not change NaCl reabsorption. We conclude that CaSR is a direct determinant of blood calcium concentration, independent of PTH, and modulates renal tubular calcium transport in the TAL via the permeability of the paracellular pathway. These findings suggest that CaSR inhibitors may provide a new specific treatment for disorders related to impaired PTH secretion, such as primary hypoparathyroidism.

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“…Thus, it appears that PTH is necessary for the maintenance of normal serum calcium concentrations when facing a hypocalcaemic challenge, but that PTH-independent mechanisms, such as CaSR-stimulated CT secretion and increased renal Ca 2C excretion, are involved in maintaining normal serum calcium concentrations in response to hypercalcaemic challenges (Kantham et al 2009).…”

Section: Pthmentioning

confidence: 99%

Mouse models for inherited endocrine and metabolic disorders

Piret

Thakker²

2011

Journal of Endocrinology

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In vivo models represent important resources for investigating the physiological mechanisms underlying endocrine and metabolic disorders, and for pre-clinical translational studies that may include the assessments of new treatments. In the study of endocrine diseases, which affect multiple organs, in vivo models provide specific advantages over in vitro models, which are limited to investigation of isolated systems. In recent years, the mouse has become the popular choice for developing such in vivo mammalian models, as it has a genome that shares w85% identity to that of man, and has many physiological systems that are similar to those in man. Moreover, methods have been developed to alter the expression of genes in the mouse, thereby generating models for human diseases, which may be due to loss-or gainof-function mutations. The methods used to generate mutations in the mouse genome include: chemical mutagenesis; conventional, conditional and inducible knockout models; knockin models and transgenic models, and these strategies are often complementary. This review describes some of the different strategies that are utilised for generating mouse models. In addition, some mouse models that have been successfully generated by these methods for some human hereditary endocrine and metabolic disorders are reviewed. In particular, the mouse models generated for parathyroid disorders, which include: the multiple endocrine neoplasias; hyperparathyroidism-jaw tumour syndrome; disorders of the calcium-sensing receptor and forms of inherited hypoparathyroidism are discussed. The advances that have been made in our understanding of the mechanisms of these human diseases by investigations of these mouse models are described.

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The calcium-sensing receptor (CaSR) defends against hypercalcemia independently of its regulation of parathyroid hormone secretion

Abstract: Kantham L, Quinn SJ, Egbuna OI, Baxi K, Butters R, Pang JL, Pollak MR, Goltzman D, Brown EM. The calcium-sensing receptor (CaSR) defends against hypercalcemia independently of its regulation of parathyroid hormone secretion.

Cited by 131 publications

References 50 publications

Claudin-14 Underlies Ca++-Sensing Receptor–Mediated Ca++ Metabolism via NFAT-microRNA–Based Mechanisms

Claudin-14 Underlies Ca++-Sensing Receptor–Mediated Ca++ Metabolism via NFAT-microRNA–Based Mechanisms

PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor

Mouse models for inherited endocrine and metabolic disorders

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