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Claudin-14 Gene Polymorphisms and Urine Calcium Excretion

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Claudin-14 Gene Polymorphisms and Urine Calcium Excretion Article Claudin-14 Gene Polymorphisms and Urine Calcium Excretion Teresa Arcidiacono,1 Marco Simonini,1 Chiara Lanzani,1 Lorena Citterio,1 Erika Salvi,2,3 Cristina Barlassina,2,3 Donatella Spotti,1 Daniele Cusi,2,3 Paolo Manunta,1 and Giuseppe Vezzoli1 Abstract Background and objectives Claudin-16 and -19 are proteins forming pores for the paracellular reabsorption of 1Nephrology and divalent cations in the ascending limb of Henle loop; conversely, claudin-14 decreases ion permeability of these claudin-14 Dialysis Unit, IRCCS pores. Single-nucleotide polymorphisms in gene coding for were associated with kidney stones and San Raffaele Scientific calcium excretion. This study aimed to explore the association of claudin-14, claudin-16,andclaudin-19 single- Institute, Genomics of nucleotide polymorphisms with calcium excretion. Renal Diseases and Hypertension Unit, Vita Salute San Design, setting, participants, & measurements We performed a retrospective observational study of 393 patients Raffaele University, with hypertension who were naïve to antihypertensive drugs, in whom we measured 24-hour urine calcium Milan, Italy; excretion; history of kidney stones was ascertained by interview; 370 of these patients underwent an intravenous 2Department of Health 0.9% sodium chlorideinfusion (2 Lin 2hours)to evaluatethe response ofcalcium excretionin three different 2-hour Sciences, University of Milan, Milan, Italy; urine samples collected before, during, and after saline infusion. Genotypes of claudin-14, claudin-16,andclaudin- 3 19 and Filarete were obtained from data of a previous genome-wide association study in the same patients. Foundation, Milan, Italy Results Thirty-one single-nucleotide polymorphisms of the 39 region of the claudin-14 gene were significantly associated with 24-hour calcium excretion and calcium excretion after saline infusion. The most significant Correspondence: associated single-nucleotide polymorphism was rs219755 (24-hour calcium excretion in GG, 2256124 mg/24 Dr. Giuseppe Vezzoli, Nephrology and hours; 24-hour calcium excretion in GA, 1946100 mg/24 hours; 24-hour calcium excretion in AA, 124673 mg/24 P, 6 Dialysis Unit, IRCCS hours; 0.001; calcium excretion during saline infusion in GG, 30 21 mg/2 hours; calcium excretion during San Raffaele Scientific saline infusion in GA, 29618 mg/2 hours; calcium excretion during saline infusion in AA, 17611 mg/2 hours; Institute, Via Olgettina P=0.03). No significant associations were found among claudin-16 and claudin-19 single-nucleotide polymor- 60, 20142 Milan, Italy. phisms and calcium excretion and between claudin-14, claudin-16,andclaudin-19 single-nucleotide polymor- Email: vezzoli. [email protected] phisms and stones. Bioinformatic analysis showed that one single-nucleotide polymorphism at claudin-14 among those associated with calcium excretion may potentially influence splicing of transcript. Conclusions Claudin-14 genotype at the 39 region is associated with calcium excretion in 24-hour urine and after the calciuretic stimulus of saline infusion. Clin J Am Soc Nephrol 13: 1542–1549, 2018. doi: https://doi.org/10.2215/CJN.01770218 Introduction junction pores in the cortex and the outer stripe of Claudins (CLDNs) are a family of transmembrane outer medulla (6). Conversely, CLDN14 may interact proteins that interact with each other and other with CLDN16 to inhibit permeability of tight junctions proteins to form barriers or pores regulating para- to calcium and magnesium (2,5,7). Interestingly, di- cellular solute transport in tight junctions (1–4). etary calcium load and extracellular calcium may Different CLDNs are expressed in specific segments stimulate CLDN14 expression in the thick ascending of the kidney tubule and contribute to the develop- limb through the activation of a calcium-sensing ment of distinctive properties of each tubular portion receptor (7,8), which may inhibit the transcription of (2,3). The thick ascending limb of the Henle loop two microRNAs (miRs; miR-9 and miR-374) suppress- reabsorbs 25% of filtered calcium through a passive ing CLDN14 gene (21q22) expression (9,10). Calcium- paracellular pathway involving CLDN14, CLDN16, sensing receptor may also slow down CLDN16 and CLDN19 (2,5). CLDN16 and CLDN19 interact to phosphorylation necessary for its location in tight form pores for calcium and magnesium reabsorption junctions (11,12). Therefore, extracellular calcium in tight junctions. They are distributed along the may inhibit calcium reabsorption in the ascending ascending limb according to a mosaic pattern with limb by increasing CLDN14 expression and decreas- CLDN10, which is involved in paracellular sodium ing CLDN16 activity in tight junctions (2,7,8). In reabsorption. Therefore, they may mediate calcium genetically modified mice, CLDN14 expression in magnesium reabsorption through specifictight the ascending limb was inhibited by the parathyroid 1542 Copyright © 2018 by the American Society of Nephrology www.cjasn.org Vol 13 October, 2018 Clin J Am Soc Nephrol 13: 1542–1549, October, 2018 Claudin-14 and Calcium Excretion, Arcidiacono et al. 1543 hormone (PTH) and appeared as the main target in the pathway used by PTH to increase calcium reabsorption in Table 1. Characteristics of population under study this tubular segment (13). These findings attribute to Variable Values CLDN14 and CLDN16 a crucial role in the regulation of calcium excretion (2,5). N (men/women) 393 (317/76) Single-nucleotide polymorphisms (SNPs) rs219778, Age, yr 45610 2 6 rs219779, rs219780, and rs219781 of CLDN14 were associ- Body mass index, kg/m 25.8 3 History of kidney stones, n (%) 33 (9) ated with kidney stones, calcium excretion, and bone Hypercalciuric subjects, n (%) 102 (26) mineral density in a genome-wide association study in eGFR, ml/min per 1.73 m2 94618 an Icelandic population (14). These SNPs were located in Serum creatinine, mg/dl 0.960.2 6 the 39 region of CLDN14 (last exon/intron) and in a unique Serum sodium, mmol/L 142 2 fi Serum calcium, mg/dl 9.260.4 haplotype block. These ndings were replicated in another 6 CLDN14 Urinary sodium, mmol/24 h 146 67 Icelandic population, in which rs199565725 in Urinary calcium, mg/24 h 2076115 showed the strongest association with kidney stones (15). Basal systolic BP, mm Hg 142615 This SNP was located in the intron 1, and it was in linkage Basal diastolic BP, mm Hg 91611 Basal mean BP, mm Hg 108611 with the SNPs associated with stones in the previous study. N (men/women) CLDN14 370 (301/69) SNPs rs219778 and rs219780 were also associated Urinary sodium before NaCl infusion 15.4613.6 with kidney stones in patients from the eastern part of India from 2120 to 0 min, mmol/2 h (16). Urinary sodium during NaCl infusion 52.4629.9 from 0 to 120 min, mmol/2 h Epidemiologic studies showed a disorder of calcium 6 handling in patients with hypertension and their offspring, Urinary sodium after NaCl infusion 51.5 29.0 from 120 to 240 min, mmol/2 h which was characterized by low calcium intake and in- Urinary calcium before NaCl infusion 21.7618.8 creased excretion of calcium (17–19) that may be promoted from 2120 to 0 min, mg/2 h by an excessive sodium chloride (NaCl) load (20–22). Urinary calcium during NaCl infusion 28.9619.4 CLDN14 from 0 to 120 min, mg/2 h Therefore, we assessed the association of , 6 CLDN16 CLDN19 Urinary calcium after NaCl infusion 18.4 15.2 ,and SNPs with calcium excretion in from 120 to 240 min, mg/2 h 24-hour urine and urine collected after an acute saline Mean BP increment at the end of NaCl 2.366.6 infusion in an Italian population of never-treated patients infusion, mm Hg 6 with hypertension. Mean BP increment at the end of test, 1.9 6.9 mm Hg Calcium excretion wasmeasured in 24-hoururine in 393patients Materials and Methods and 2-hour urine collections during the NaCl infusion test in 370 Patients patients. The NaCl infusion test lasted 6 hours and consisted of We enrolled 393 never-treated, recently discovered pa- three 2-h periods during which urine was collected: an equili- bration period followed by an infusion period (in which patients tients with essential hypertension with high/normal BP – were infused with 2 L of 0.9% NaCl solution) and a recovery level or grade 1 or 2 hypertension (diastolic BP range, 90 period after the infusion. 110 mm Hg; systolic BP range, 110–180 mm Hg) according to the guidelines for management of arterial hypertension (17). All patients were recruited at the Outpatient Clinic for Hypertension of San Raffaele Hospital (Milan, Italy), and they were enrolled in the HYPERGENES-InterOmics Project approved the study, which was conducted in Project studying genetic determinants of arterial hyper- adherence with the Helsinki Declaration principles. In- tension (23). Patients with secondary causes of hyperten- formed consent was obtained from each participant. sion (by biochemical and instrumental tests), endocrine disorders, body mass index .32 kg/m2,orchronicand Saline Load Test acute concomitant diseases (cardiocerebrovascular dis- Three hundred seventy subjects underwent a saline eases, diabetes mellitus, or hepatic and kidney diseases) infusion test according to the reported protocol (25). An and women taking contraceptive pills were excluded intravenous infusion of 2 L of 0.9% NaCl solution (308 from the study. Participants could not have taken thia- mmol of NaCl) was administered in 2 hours. Blood and 24- zide, vitamin D, calcium supplements, or drugs for hour urine were collected before the test (24-hour urine was osteoporosis or mineral and electrolyte metabolism. defined as baseline urine collection). Two-hour urine Glomerular filtration (eGFR) was estimated with the samples were collected immediately before the saline Chronic Kidney Disease Epidemiology Collaboration infusion (from 2120 to 0 minutes of the test; defined as equation (24) and had to be .60 ml/min per 1.73 m2. equilibration time), during the whole infusion (from 0 to All patients were studied during a free diet.
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