The calcium-sensing receptor promotes urinary acidification to prevent nephrolithiasis.
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ABSTRACT:
SUBMITTER: Renkema KY
PROVIDER: S-EPMC2723980 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND: CaSR gene is a candidate for calcium nephrolithiasis. Single-nucleotide polymorphisms (SNPs) encompassing its regulatory region were associated with calcium nephrolithiasis. AIMS: We tested SNPs in the CaSR gene regulatory region associated with calcium nephrolithiasis and their effects in kidney. SUBJECTS AND METHODS: One hundred sixty-seven idiopathic calcium stone formers and 214 healthy controls were genotyped for four CaSR gene SNPs identified by bioinformatics analysis as modifying transcription factor binding sites. Strontium excretion after an oral load was tested in 55 stone formers. Transcriptional activity induced by variant alleles at CaSR gene promoters was compared by luciferase reporter gene assay in HEK-293 and HKC-8 cells. CaSR and claudin-14 mRNA levels were measured by real-time PCR in 107 normal kidney medulla samples and compared in patients with different CaSR genotype. RESULTS: Only rs6776158 (A>G), located in the promoter 1, was associated with nephrolithiasis. Its minor G allele was more frequent in stone formers than controls (37.8% vs 26.4%, P = .001). A reduced strontium excretion was observed in GG homozygous stone formers. Luciferase fluorescent activity was lower in cells transfected with the promoter 1 including G allele at rs6776158 than cells transfected with the A allele. CaSR mRNA levels were lower in kidney medulla samples from homozygous carriers for the G allele at rs6776158 than carriers for the A allele. Claudin-14 mRNA levels were also lower in GG homozygous subjects. CONCLUSIONS: Minor allele at rs6776158 may predispose to calcium stones by decreasing transcriptional activity of the CaSR gene promoter 1 and CaSR expression in kidney tubules.
| S-EPMC3763974 | biostudies-literature
Project description:Calcium nephrolithiasis is one of the most common causes of renal stones. While the prevalence of this disease has increased steadily over the last 3 decades, its pathogenesis is still unclear. Previous studies have indicated that a genetic polymorphism (rs17251221) in the calcium-sensing receptor gene (CASR) is associated with the total serum calcium levels. In this study, we collected DNA samples from 480 Taiwanese subjects (189 calcium nephrolithiasis patients and 291 controls) for genotyping the CASR gene. Our results indicated no significant association between the CASR polymorphism (rs17251221) and the susceptibility of calcium nephrolithiasis. However, we found a significant association between rs17251221 and stone multiplicity. The risk of stone multiplicity was higher in patients with the GG+GA genotype than in those with the AA genotype (chi-square test: P?=?0.008; odds ratio ?=? 4.79; 95% confidence interval, 1.44-15.92; Yates' correction for chi-square test: P?=?0.013). In conclusion, our results provide evidence supporting the genetic effects of CASR on the pathogenesis of calcium nephrolithiasis.
| S-EPMC3178627 | biostudies-literature
Project description:Nephrolithiasis, secondary hyperparathyroidism (sHPT), and cardiovascular complications are associated with disturbances in Ca handling and contribute to morbidity/mortality during haemodialysis (HD). Calcimimetics, activators of the calcium-sensing receptor (CaSR), provide an effective means of reducing parathyroid hormone (PTH) secretion in sHPT. Polymorphism in CaSR gene (CASR) influences Ca-related parameters, however it was not shown in HD patients for CASR rs7652589. The minor allele at this polymorphism modifies the binding sites of transcription factors and CaSR expression. We hypothesized that CASR rs7652589 variants may also influence CaSR in end stage renal disease (ESRD). We aimed to determine the associations of rs7652589 with nephrolithiasis-related ESRD, Ca, P, ALP, PTH, response to treatment with cinacalcet, prevalence of coronary artery disease, and all-cause/cardiovascular mortality in HD patients (n?=?1162). Healthy individuals (n?=?918) were controls. This study shows that the A allele of rs7652589 is a risk allele for nephrolithiasis-related ESRD. The AA genotype is associated with more severe sHPT (higher Ca and PTH concentrations). The A allele is associated with reduced CaSR transcript level in peripheral blood mononuclear cells. According to computational analysis, potential binding sites for GLI3, AHR and TP53 are removed by the A allele, whereas binding sites for SOX18 and TP63 are created.
| S-EPMC5064403 | biostudies-literature
Project description:Calcium binding to the Ca-sensing receptor (CASR) expressed in thick ascending limb inhibits the Na,K,2Cl cotransporter, which decreases sodium reabsorption and secondarily decreases Ca reabsorption. CASR gene variants could influence blood pressure (BP) by affecting Na retention.The objective of the study was to determine whether variations in CASR associated with BP in African-Americans, an ethnic group at high risk for hypertension.Population- and family-based association studies of single-nucleotide polymorphisms (SNPs) in CASR with BP measured over the age range 5.6-25 yr (14 biannual visits per subject on average) were carried out. In a cross-sectional study where urinary Ca excretion had been measured, Ca excretion was used as an additional phenotype of CASR influence on Na,K,2Cl cotransporter activity.Subjects were normotensive. In the longitudinal study, there were 223 subjects (mean age 14 yr) and 123 families (one or both parents provided a DNA sample); in the cross-sectional study, there were 106 subjects (mean age 23 yr) and 88 families.Three SNPs in linkage disequilibrium associated with systolic BP at P < 0.005 (the significance threshold corrected for multiple comparisons) in the population-based longitudinal study. In the cross-sectional study, SNPs contained in the same linkage disequilibrium block associated with urinary Ca excretion in both population- and family-based association studies.The findings suggest that in African-Americans, functional heterogeneity of the CASR in thick ascending limb may influence BP.
| S-EPMC2681276 | biostudies-literature
Project description:Whether GPCRs support the sensing of temperature as well as other chemical and physical modalities is not well understood. Introduction: Extracellular Ca2+ concentration (Ca2+ o) modulates core body temperature and the firing rates of temperature-sensitive CNS neurons, and hypocalcemia provokes childhood seizures. However, it is not known whether these phenomena are mediated by Ca2+ o-sensing GPCRs, including the calcium-sensing receptor (CaSR). In favor of the hypothesis, CaSRs are expressed in hypothalamic regions that support core temperature regulation, and autosomal dominant hypocalcemia, due to CaSR activating mutations, is associated with childhood seizures. Methods: Herein, we tested whether CaSR-dependent signaling is temperature sensitive using an established model system, CaSR-expressing HEK-293 cells. Results: We found that the frequency of Ca2+ o-induced Ca2+ i oscillations but not the integrated response was linearly dependent on temperature in a pathophysiologically relevant range. Chimeric receptor analysis showed that the receptor's C-terminus is required for temperature-dependent modulation and experiments with the PKC inhibitor GF109203X and CaSR mutants T888A and T888M, which eliminate a key phosphorylation site, demonstrated the importance of repetitive phosphorylation and dephosphorylation. Discussion and Conclusion: CaSRs mediate temperature-sensing and the mechanism, dependent upon repetitive phosphorylation and dephosphorylation, suggests that GPCRs more generally contribute to temperature-sensing.
| S-EPMC9931745 | biostudies-literature
Project description:Calcium nephrolithiasis may be considered as a complex disease having multiple pathogenetic mechanisms and characterized by various clinical manifestations. Both genetic and environmental factors may increase susceptibility to calcium stones; therefore, it is crucial to characterize the patient phenotype to distinguish homogeneous groups of stone formers. Family and twin studies have shown that the stone transmission pattern is not mendelian, but complex and polygenic. In these studies, heritability of calcium stones was calculated around 50%Calcium-sensing receptor (CaSR) is mostly expressed in the parathyroid glands and in renal tubules. It regulates the PTH secretion according to the serum calcium concentration. In the kidney, it modulates electrolyte and water excretion regulating the function of different tubular segments. In particular, CaSR reduces passive and active calcium reabsorption in distal tubules, increases phosphate reabsorption in proximal tubules and stimulates proton and water excretion in collecting ducts. Therefore, it is a candidate gene for calcium nephrolithiasis.In a case-control study we found an association between the normocitraturic stone formers and two SNPs of CaSR, located near the promoters region (rs7652589 and rs1501899). This result was replicated in patients with primary hyperparathyroidism, comparing patients with or without kidney stones. Bioinformatic analysis suggested that the minor alleles at these polymorphisms were able to modify the binding sites of specific transcription factors and, consequently, CaSR expression.Our studies suggest that CaSR is one of the candidate genes explaining individual predisposition to calcium nephrolithiasis. Stone formation may be favored by an altered CaSR expression in kidney medulla involving the normal balance among calcium, phosphate, protons and water excretion.
| S-EPMC3339356 | biostudies-literature
Project description:Bone metastasis is an important prognostic factor in renal cell carcinoma (RCC). The calcium-sensing receptor (CaSR) has been associated with bone metastasis in several different malignancies. We analyzed the impact of CaSR in bone metastasis in RCC in vitro and in vivo. The RCC cell line 786-O was stably transfected with the CaSR gene and treated with calcium alone or in combination with the CaSR antagonist NPS2143. Afterwards migration, adhesion, proliferation and prominent signaling molecules were analyzed. Calcium treated CaSR-transfected 768-O cells showed an increased adhesion to endothelial cells and the extracellular matrix components fibronectin and collagen I, but not to collagen IV. The chemotactic cell migration and proliferation was also induced by calcium. The activity of SHC, AKT, ERK, P90RSK and JNK were enhanced after calcium treatment of CaSR-transfected cells. These effects were abolished by NPS2143. Development of bone metastasis was evaluated in vivo in a mouse model. Intracardiac injection of CaSR-transfected 768-O cells showed an increased rate of bone metastasis. The results indicate CaSR as an important component in the mechanism of bone metastasis in RCC. Therefore, targeting CaSR might be beneficial in patients with bone metastatic RCC with a high CaSR expression.
| S-EPMC5884663 | biostudies-literature
Project description:The calcium-sensing receptor (CaSR) plays a pivotal role in systemic calcium metabolism by regulating parathyroid hormone secretion and urinary calcium excretion. The diseases caused by an abnormality of the CaSR are genetically determined or are more rarely acquired. The genetic diseases consist of hyper- or hypocalcemia disorders. Hypercalcaemia disorders are related to inactivating mutations of the CASR gene either heterozygous (autosomal dominant familial benign hypercalcaemia, still named hypocalciuric hypercalcaemia syndrome type 1) or homozygous (severe neonatal hyperparathyroidism). The A986S, R990G and Q1011E variants of the CASR gene are associated with higher serum calcium levels than in the general population, hypercalciuria being also associated with the R990G variant. The differential diagnosis consists in the hypocalciuric hypercalcaemia syndrome, types 2 (involving GNA11 gene) and 3 (involving AP2S1 gene); hyperparathyroidism; abnormalities of vitamin D metabolism, involving CYP24A1 and SLC34A1 genes; and reduced GFR. Hypocalcemia disorders, which are more rare, are related to heterozygous activating mutations of the CASR gene (type 1), consisting of autosomal dominant hypocalcemia disorders, sometimes with a presentation of pseudo-Bartter's syndrome. The differential diagnosis consists of the hypercalciuric hypocalcaemia syndrome type 2, involving GNA11 gene and other hypoparathyroidism aetiologies. The acquired diseases are related to the presence of anti-CaSR antibodies, which can cause hyper- or especially hypocalcemia disorders (for instance in APECED syndromes), determined by their functionality. Finally, the role of CaSR in digestive, respiratory, cardiovascular and neoplastic diseases is gradually coming to light, providing new therapeutic possibilities. Two types of CaSR modulators are known: CaSR agonists (or activators, still named calcimimetics) and calcilytic antagonists (or inhibitors of the CasR). CaSR agonists, such as cinacalcet, are indicated in secondary and primary hyperparathyroidism. Calcilytics have no efficacy in osteoporosis, but could be useful in the treatment of hypercalciuric hypocalcaemia syndromes.
| S-EPMC5264458 | biostudies-literature
Project description:Parathyroid hormone-related protein (PTHrP) contributes to the development and metastatic progression of breast cancer by promoting hypercalcemia, tumor growth, and osteolytic bone metastases, but it is not known how PTHrP is upregulated in breast tumors. Here we report a central role in this process for the calcium-sensing receptor, CaSR, which enables cellular responses to changes in extracellular calcium, through studies of CaSR-PTHrP interactions in the MMTV-PymT transgenic mouse model of breast cancer and in human breast cancer cells. CaSR activation stimulated PTHrP production by breast cancer cells in vitro and in vivo Tissue-specific disruption of the casr gene in mammary epithelial cells in MMTV-PymT mice reduced tumor PTHrP expression and inhibited tumor cell proliferation and tumor outgrowth. CaSR signaling promoted the proliferation of human breast cancer cell lines and tumor cells cultured from MMTV-PyMT mice. Further, CaSR activation inhibited cell death triggered by high extracellular concentrations of calcium. The actions of the CaSR appeared to be mediated by nuclear actions of PTHrP that decreased p27(kip1) levels and prevented nuclear accumulation of the proapoptotic factor apoptosis inducing factor. Taken together, our findings suggest that CaSR-PTHrP interactions might be a promising target for the development of therapeutic agents to limit tumor cell growth in bone metastases and in other microenvironments in which elevated calcium and/or PTHrP levels contribute to breast cancer progression. Cancer Res; 76(18); 5348-60. ©2016 AACR.
| S-EPMC5026591 | biostudies-literature
Project description:Hypercalciuria is a major risk factor for nephrolithiasis. We previously reported that Uromodulin (UMOD) protects against nephrolithiasis by upregulating the renal calcium channel TRPV5. This channel is crucial for calcium reabsorption in the distal convoluted tubule (DCT). Recently, mutations in the gene encoding Mucin-1 (MUC1) were found to cause autosomal dominant tubulointerstitial kidney disease, the same disease caused by UMOD mutations. Because of the similarities between UMOD and MUC1 regarding associated disease phenotype, protein structure, and function as a cellular barrier, we examined whether urinary MUC1 also enhances TRPV5 channel activity and protects against nephrolithiasis. We established a semiquantitative assay for detecting MUC1 in human urine and found that, compared with controls (n=12), patients (n=12) with hypercalciuric nephrolithiasis had significantly decreased levels of urinary MUC1. Immunofluorescence showed MUC1 in the thick ascending limb, DCT, and collecting duct. Applying whole-cell patch-clamp recording of HEK cells, we found that wild-type but not disease mutant MUC1 increased TRPV5 activity by impairing dynamin-2- and caveolin-1-mediated endocytosis of TRPV5. Coimmunoprecipitation confirmed a physical interaction between TRPV5 and MUC1. However, MUC1 did not increase the activity of N-glycan-deficient TRPV5. MUC1 is characterized by variable number tandem repeats (VNTRs) that bind the lectin galectin-3; galectin-3 siRNA but not galectin-1 siRNA prevented MUC1-induced upregulation of TRPV5 activity. Additionally, MUC1 lacking VNTRs did not increase TRPV5 activity. Our results suggest that MUC1 forms a lattice with the N-glycan of TRPV5 via galectin-3, which impairs TRPV5 endocytosis and increases urinary calcium reabsorption.
| S-EPMC5084893 | biostudies-other