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Permanent link (DOI): https://doi.org/10.7939/R32K9R

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Deciphering the Claudins that Mediate Renal Calcium Reabsorption Open Access

Descriptions

Other title
Subject/Keyword
Kidney Stones
Osteoporosis
Claudins
Calcium
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Desai, Prajakta V
Supervisor and department
Alexander, Todd (Paediatrics)
Examining committee member and department
Cheung, Po-Yin (Paediatrics)
Braam, Branko (Physiology)
Department
Medical Sciences-Paediatrics
Specialization

Date accepted
2012-07-11T15:41:24Z
Graduation date
2012-11
Degree
Master of Science
Degree level
Master's
Abstract
Kidney stones and osteoporosis are prevalent clinical conditions posing a large economic burden to the healthcare system. A common risk factor for both these diseases is hypercalciuria, which is the inappropriate excretion of calcium in urine. Changes in serum calcium levels are detected by the calcium sensing receptor (CaSR). In the kidney, the CaSR is localized in tubular segments where calcium (Ca2+) flux occurs via the paracellular pathway, specifically the proximal tubule and the thick ascending limb of Henle’s loop (TAL). Claudins are proteins localized in the tight junction of epithelia that control paracellular ion flux. Recently, claudin-14 (Cldn14) expression was observed in the TAL. We found that Cldn14 is regulated by dietary Ca2+ intake and by elevated serum Ca2+ levels after prolonged 1,25-dihydroxyvitamin D3 administration in mice. Consistent with this, in vivo activation of the CaSR by administration of the calcimimetic Cinacalcet, lead to a 40-fold increase in Cldn14 mRNA abundance. Overexpression of Cldn14 in a renal tubular cell culture model inhibited paracellular Ca2+ flux. Together the data suggests that when serum Ca2+ level increases it activates the CaSR leading to increased Cldn14 expression in the TAL. This in turn blocks Ca2+ reabsorption and induces calciuria. Dysregulation of this newly described CaSR-Cldn14 axis likely contributes to the development of hypercalciuria and kidney stones.
Language
English
DOI
doi:10.7939/R32K9R
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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