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

Gong, Y.; Hou, Jianghui

doi:10.1681/asn.2013050553

Cited by 87 publications

(110 citation statements)

References 45 publications

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“…81 The signaling mechanism seems to involve CaSR somehow inhibiting calcineurin, a phosphatase that normally activates NFAT to increase transcription of two micro-RNAs (miR-9 and miR-374), thereby downregulating claudin-14 expression. 81,83 The central role of claudin-14 is supported by the striking observation that claudin-14 knockout mice are unable to increase their fractional excretion of calcium in response to a high-Ca 2+ diet 81 and exhibit complete loss of regulation of urinary Ca 2+ excretion in response to a CaSR agonist or antagonist. 83 …”

Section: Regulation Of Tal Claudins By Extracellular Calciummentioning

confidence: 99%

“…81,83 The central role of claudin-14 is supported by the striking observation that claudin-14 knockout mice are unable to increase their fractional excretion of calcium in response to a high-Ca 2+ diet 81 and exhibit complete loss of regulation of urinary Ca 2+ excretion in response to a CaSR agonist or antagonist. 83 …”

Section: Regulation Of Tal Claudins By Extracellular Calciummentioning

confidence: 99%

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Claudins and the Kidney

2015

Journal of the American Society of Nephrology

126

100

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Claudins are tight-junction membrane proteins that function as both pores and barriers in the paracellular pathway in epithelial cells. In the kidney, claudins determine the permeability and selectivity of different nephron segments along the renal tubule. In the proximal tubule, claudins have a role in the bulk reabsorption of salt and water. In the thick ascending limb, claudins are important for the reabsorption of calcium and magnesium and are tightly regulated by the calcium-sensing receptor. In the distal nephron, claudins need to form cation barriers and chloride pores to facilitate electrogenic sodium reabsorption and potassium and acid secretion. Aldosterone and the with-no-lysine (WNK) proteins likely regulate claudins to fine-tune distal nephron salt transport. Genetic mutations in claudin-16 and -19 cause familial hypomagnesemic hypercalciuria with nephrocalcinosis, whereas polymorphisms in claudin-14 are associated with kidney stone risk. It is likely that additional roles for claudins in the pathogenesis of other types of kidney diseases have yet to be uncovered.

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Section: Regulation Of Tal Claudins By Extracellular Calciummentioning

confidence: 99%

Section: Regulation Of Tal Claudins By Extracellular Calciummentioning

confidence: 99%

Claudins and the Kidney

2015

Journal of the American Society of Nephrology

126

100

View full text Add to dashboard Cite

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“…This suggested that claudin-14 expression in the TALH was under the control of the extracellular calcium through the calcium-sensing receptor (CaSR) [22,24]. In mice, CaSR activation upregulated claudin-14 expression through a histone deacetylation mechanism mediated by the nuclear factor of activated T cells (NFAT) that inhibited the production of two microRNAs, miR-9, and miR-374, modulating the CLDN14 transcription [22,25]. Claudin-14 may thus regulate calcium reabsorption in response to calcium intake.…”

Section: The Cldn14 Genementioning

confidence: 99%

“…Interestingly, the larger part of SNPs associated with stones may change gene expression and could consequently modify nutrient effect on gene expression. An example is the epigenetic activation of claudin-14 expression by calcium intake mediated by microRNAs [25], but other studies are needed to explore the interaction between genes and nutrients and to understand better gene involvement in kidney stone production.…”

Section: Genetic Polymorphisms and Lithogenic Mechanismsmentioning

confidence: 99%

Idiopathic Calcium Nephrolithiasis: A Review of Pathogenic Mechanisms in the Light of Genetic Studies

et al. 2014

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Background: Calcium nephrolithiasis is a multifactorial disease with a polygenic milieu. Association studies identified genetic polymorphisms potentially implicated in the pathogenesis of calcium nephrolithiasis. The present article reviews the mechanisms of calcium stone formation and the potential contribution of gene polymorphisms to lithogenic mechanisms. Summary: Endoscopy observations suggested that precipitation of calcium-oxalate on the Randall's plaque at the papilla surface may cause idiopathic calcium-oxalate stones. The Randall's plaque is a hydroxyapatite deposit in the interstitium of the kidney medulla, which resembles a soft tissue calcification. Conversely, calcium-phosphate stones may develop from crystalline deposits located at the tip of the Bellini duct. Polymorphisms of eleven genes have been associated with stones in genome-wide association studies and replicated candidate-gene association studies: VDR, SLC34A1, SLC34A4, CLDN14, and CaSR genes coding for proteins regulating tubular phosphate and calcium reabsorption; CaSR, MGP, OPN, PLAU, and UMOD genes coding for proteins preventing calcium salt precipitation; AQP1 gene coding for a water channel in the proximal tubule. The renal activity of the last gene, DGKH, is unknown. Polymorphisms in these genes may predispose to calcium-oxalate and -phosphate stones by increasing the risk of calcium-phosphate precipitation in the tubular fluid. Key Messages: Genetic findings suggest that tubular fluid supersaturation with respect to calcium and phosphate predisposes to calcium-oxalate stones by triggering cellular mechanisms that lead to the Randall's plaque formation. © 2014 S. Karger AG, Basel

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“…These signal transduction events allow the parathyroid CaSR to respond to small fluctuations in the prevailing extracellular calcium concentration ([Ca 2+ ] o ) by inducing alterations in PTH secretion through mechanisms that likely involve effects on PTH mRNA stability7 and PTH granule exocytosis from the apical pole of parathyroid cells 8. Moreover, the kidney CaSR is considered to influence urinary calcium excretion by modulating expression of claudin proteins that mediate the paracellular reabsorption of calcium in the renal thick ascending limb 9, 10. FHH2 (OMIM #145981) is the result of loss‐of‐function mutations in the G‐protein subunit‐α11 (Gα 11 ), encoded by GNA11 , and to date only two FHH2‐associated Gα 11 missense mutations have been reported (Fig.…”

Section: Introductionmentioning

confidence: 99%

A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)

Gorvin

Cranston

Hannan

et al. 2016

Journal of Bone and Mineral Research

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Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogeneous disorder with three variants, FHH1 to FHH3. FHH1 is caused by loss‐of‐function mutations of the calcium‐sensing receptor (CaSR), a G‐protein coupled receptor that predominantly signals via G‐protein subunit alpha‐11 (Gα11) to regulate calcium homeostasis. FHH2 is the result of loss‐of‐function mutations in Gα11, encoded by GNA11, and to date only two FHH2‐associated Gα11 missense mutations (Leu135Gln and Ile200del) have been reported. FHH3 is the result of loss‐of‐function mutations of the adaptor protein‐2 σ‐subunit (AP2σ), which plays a pivotal role in clathrin‐mediated endocytosis. We describe a 65‐year‐old woman who had hypercalcemia with normal circulating parathyroid hormone concentrations and hypocalciuria, features consistent with FHH, but she did not have CaSR and AP2σ mutations. Mutational analysis of the GNA11 gene was therefore undertaken, using leucocyte DNA, and this identified a novel heterozygous GNA11 mutation (c.161C>T; p.Thr54Met). The effect of the Gα11 variant was assessed by homology modeling of the related Gαq protein and by measuring the CaSR‐mediated intracellular calcium (Ca2+ i) responses of HEK293 cells, stably expressing CaSR, to alterations in extracellular calcium (Ca2+ o) using flow cytometry. Three‐dimensional modeling revealed the Thr54Met mutation to be located at the interface between the Gα11 helical and GTPase domains, and to likely impair GDP binding and interdomain interactions. Expression of wild‐type and the mutant Gα11 in HEK293 cells stably expressing CaSR demonstrate that the Ca2+ i responses after stimulation with Ca2+ o of the mutant Met54 Gα11 led to a rightward shift of the concentration‐response curve with a significantly (p < 0.01) increased mean half‐maximal concentration (EC50) value of 3.88 mM (95% confidence interval [CI] 3.76–4.01 mM), when compared with the wild‐type EC50 of 2.94 mM (95% CI 2.81–3.07 mM) consistent with a loss‐of‐function. Thus, our studies have identified a third Gα11 mutation (Thr54Met) causing FHH2 and reveal a critical role for the Gα11 interdomain interface in CaSR signaling and Ca2+ o homeostasis. © 2016 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).

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

Cited by 87 publications

References 45 publications

Claudins and the Kidney

Claudins and the Kidney

Idiopathic Calcium Nephrolithiasis: A Review of Pathogenic Mechanisms in the Light of Genetic Studies

A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)

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