A variant in a cis
-regulatory element enhances claudin-14 expression and is associated with pediatric-onset hypercalciuria and kidney stones

Abstract Objective To Compare a nanobacterial (NB) rat kidney stone model and the traditional ethylene glycol (EG) rat kidney stone model to assess its significance. Methods Ninety Wistar male rats were randomly divided into three groups. After the first week of modeling, three rats of every groups were randomly selected to measure the biochemical blood and urine markers. After the sacrifice, the renal tissues were observed to assess the pathological changes. The expression levels of CaSR and Claudin-14 protein were detected by kinds of technology. Results The biochemical metabolic indices of rats in NB group began to increase at the third week and decreased to normal at the 9th week. In the EG group they began to increase at the second week and did not return to normal later. At the 7th week, the creatinine levels of rats in the EG group were higher than in the NB group, and the difference was statistically significant. The formation rates of kidney stones in the NB group and EG group were 52.4 and 66.7%, respectively, but the difference of the two rates was not statistically significant. The protein expression CaSR and Claudin-14 in the EG group began to strengthen at 3rd week, and at 4th week in the NB group. CaSR was continuously expressed in the NC group, but Claudin-14 was not expressed. Conclusion The formation of stones in the NB group began slightly later. CaSR and Claudin-14 proteins play a role in the formation of kidney stones.

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Activation of the Ca2+-sensing receptor increases renal claudin-14 expression and urinary Ca2+ excretion

AJP Renal Physiology ◽

10.1152/ajprenal.00263.2012 ◽

2013 ◽

Vol 304 (6) ◽

pp. F761-F769 ◽

Cited By ~ 59

Author(s):

Henrik Dimke ◽

Prajakta Desai ◽

Jelena Borovac ◽

Alyssa Lau ◽

Wanling Pan ◽

...

Keyword(s):

Kidney Stones ◽

Elevated Serum ◽

Fold Increase ◽

Thick Ascending Limb ◽

Dihydroxyvitamin D ◽

Cation Permeability ◽

Culture Models ◽

Cinacalcet Hydrochloride ◽

Claudin 14

Kidney stones are a prevalent clinical condition imposing a large economic burden on the healthcare system. Hypercalciuria remains the major risk factor for development of a Ca2+-containing stone. The kidney's ability to alter Ca2+ excretion in response to changes in serum Ca2+ is in part mediated by the Ca2+-sensing receptor (CaSR). Recent studies revealed renal claudin-14 (Cldn14) expression localized to the thick ascending limb (TAL) and its expression to be regulated via the CaSR. We find that Cldn14 expression is increased by high dietary Ca2+ intake and by elevated serum Ca2+ levels induced by prolonged 1,25-dihydroxyvitamin D3 administration. Consistent with this, activation of the CaSR in vivo via administration of the calcimimetic cinacalcet hydrochloride led to a 40-fold increase in Cldn14 mRNA. Moreover, overexpression of Cldn14 in two separate cell culture models decreased paracellular Ca2+ flux by preferentially decreasing cation permeability, thereby increasing transepithelial resistance. These data support the existence of a mechanism whereby activation of the CaSR in the TAL increases Cldn14 expression, which in turn blocks the paracellular reabsorption of Ca2+. This molecular mechanism likely facilitates renal Ca2+ losses in response to elevated serum Ca2+. Moreover, dysregulation of the newly described CaSR-Cldn14 axis likely contributes to the development of hypercalciuria and kidney stones.

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MP07-07 PRELIMINARY STUDY ON THE ROLE OF SELECTIVE REGULATION OF CaSR-CLAUDIN-14 PATHWAY IN THE FORMATION OF CALCIUM OXALATE KIDNEY STONES IN RATS

The Journal of Urology ◽

10.1097/ju.0000000000001980.07 ◽

2021 ◽

Vol 206 (Supplement 3) ◽

Author(s):

Biao Qian ◽

Zhiqiang Hao ◽

Jingshen Wang ◽

Xiaofeng Zou ◽

Guoxi Zhang ◽

...

Keyword(s):

Calcium Oxalate ◽

Kidney Stones ◽

Preliminary Study ◽

Claudin 14

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Claudin-14 Gene Polymorphisms and Urine Calcium Excretion

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.01770218 ◽

2018 ◽

Vol 13 (10) ◽

pp. 1542-1549 ◽

Cited By ~ 5

Author(s):

Teresa Arcidiacono ◽

Marco Simonini ◽

Chiara Lanzani ◽

Lorena Citterio ◽

Erika Salvi ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Kidney Stones ◽

Saline Infusion ◽

Calcium Excretion ◽

Nucleotide Polymorphisms ◽

Nucleotide Polymorphism ◽

Urine Calcium ◽

Single Nucleotide ◽

Urine Calcium Excretion ◽

Claudin 14

Background and objectivesClaudin-16 and -19 are proteins forming pores for the paracellular reabsorption of divalent cations in the ascending limb of Henle loop; conversely, claudin-14 decreases ion permeability of these pores. Single-nucleotide polymorphisms in gene coding for claudin-14 were associated with kidney stones and calcium excretion. This study aimed to explore the association of claudin-14, claudin-16, and claudin-19 single-nucleotide polymorphisms with calcium excretion.Design, setting, participants, & measurementsWe performed a retrospective observational study of 393 patients with hypertension who were naïve to antihypertensive drugs, in whom we measured 24-hour urine calcium excretion; history of kidney stones was ascertained by interview; 370 of these patients underwent an intravenous 0.9% sodium chloride infusion (2 L in 2 hours) to evaluate the response of calcium excretion in three different 2-hour urine samples collected before, during, and after saline infusion. Genotypes of claudin-14, claudin-16, and claudin-19 were obtained from data of a previous genome-wide association study in the same patients.ResultsThirty-one single-nucleotide polymorphisms of the 3′ region of the claudin-14 gene were significantly associated with 24-hour calcium excretion and calcium excretion after saline infusion. The most significant associated single-nucleotide polymorphism was rs219755 (24-hour calcium excretion in GG, 225±124 mg/24 hours; 24-hour calcium excretion in GA, 194±100 mg/24 hours; 24-hour calcium excretion in AA, 124±73 mg/24 hours; P<0.001; calcium excretion during saline infusion in GG, 30±21 mg/2 hours; calcium excretion during saline infusion in GA, 29±18 mg/2 hours; calcium excretion during saline infusion in AA, 17±11 mg/2 hours; P=0.03). No significant associations were found among claudin-16 and claudin-19 single-nucleotide polymorphisms and calcium excretion and between claudin-14, claudin-16, and claudin-19 single-nucleotide polymorphisms 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.ConclusionsClaudin-14 genotype at the 3′ region is associated with calcium excretion in 24-hour urine and after the calciuretic stimulus of saline infusion.

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