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Deciphering the Claudins that Mediate Renal Calcium Reabsorption

  • Author / Creator
    Desai, Prajakta V
  • 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.

  • Subjects / Keywords
  • Graduation date
    2012-11
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/R32K9R
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Master's
  • Department
    • Medical Sciences-Paediatrics
  • Supervisor / co-supervisor and their department(s)
    • Alexander, Todd (Paediatrics)
  • Examining committee members and their departments
    • Braam, Branko (Physiology)
    • Cheung, Po-Yin (Paediatrics)