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Molecular mechanisms altering tubular calcium reabsorption

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Abstract

The majority of calcium filtered by the glomerulus is reabsorbed along the nephron. Most is reabsorbed from the proximal tubule (> 60%) via a paracellular pathway composed of the tight junction proteins claudins-2 and -12, a process driven by sodium and consequently water reabsorption. The thick ascending limb reabsorbs the next greatest amount of calcium (20–25%), also by a paracellular pathway composed of claudins-16 and -19. This pathway is regulated by the CaSR, whose activity increases the expression of claudin-14, a protein that blocks paracellular calcium reabsorption. The fine tuning of urinary calcium excretion occurs in the distal convoluted and connecting tubule by a transcellular pathway composed of the apical calcium channel TRPV5, the calcium shuttling protein calbindin-D28K and the basolateral proteins PMCA1b and the sodium calcium exchanger, NCX. Not surprisingly, mutations in a subset of these genes cause monogenic disorders with hypercalciuria as a part of the phenotype. More commonly, “idiopathic” hypercalciuria is encountered clinically with genetic variations in CLDN14, the CASR and TRPV5 associating with kidney stones and increased urinary calcium excretion. An understanding of the molecular pathways conferring kidney tubular calcium reabsorption is employed in this review to help explain how dietary and medical interventions for this disorder lower urinary calcium excretion.

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Funding

ML Downie is funded by the Canadian Kidney Research Scientist and Core Education Training Program (KRESCENT) as well as the St. Peter’s Trust for Kidney, Bladder & Prostate Research. Research in the Alexander laboratory is funded by grants from the Women and Children’s Health Research Institute, which is supported by the Stollery Children’s Hospital Foundation, the Canadian Institutes of Health Research, the Kidney Foundation of Canada and the National Sciences and Engineering Research Council of Canada. Dr. Alexander is a Stollery Science laboratory Distinguished Researcher and the Canada Research Chair in Renal Epithelial Transport Physiology.

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Authors and Affiliations

  1. Department of Renal Medicine, University College London, London, UK

    Mallory L Downie

  2. Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK

    Mallory L Downie

  3. Department of Paediatrics, The University of Alberta, Edmonton, Alberta, T6G 2R7, Canada

    R. Todd Alexander

  4. The Women’s & Children’s Health Research Institute, Edmonton, Alberta, Canada

    R. Todd Alexander

  5. Department of Pediatrics, Division of Pediatric Nephrology, University of Alberta, 4-585 Edmonton Clinic Health Academy, Edmonton, Alberta, T6G 1C9, Canada

    R. Todd Alexander

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  1. Mallory L Downie
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Correspondence to R. Todd Alexander.

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Dr. Alexander has received consulting fees or honoraria from Ardylex, Ultragenyx and Advicenne. Dr. Downie has no conflicts to declare.

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Downie, M.L., Alexander, R.T. Molecular mechanisms altering tubular calcium reabsorption. Pediatr Nephrol 37, 707–718 (2022). https://doi.org/10.1007/s00467-021-05049-0

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