Deletion of claudin-10 rescues claudin-16-deficient mice from hypomagnesemia and hypercalciuria

Kidney Int. 2018 Mar;93(3):580-588. doi: 10.1016/j.kint.2017.08.029. Epub 2017 Nov 10.


The tight junction proteins claudin-10 and -16 are crucial for the paracellular reabsorption of cations along the thick ascending limb of Henle's loop in the kidney. In patients, mutations in CLDN16 cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis, while mutations in CLDN10 impair kidney function. Mice lacking claudin-16 display magnesium and calcium wasting, whereas absence of claudin-10 results in hypermagnesemia and interstitial nephrocalcinosis. In order to study the functional interdependence of claudin-10 and -16 we generated double-deficient mice. These mice had normal serum magnesium and urinary excretion of magnesium and calcium and showed polyuria and sodium retention at the expense of increased renal potassium excretion, but no nephrocalcinosis. Isolated thick ascending limb tubules of double mutants displayed a complete loss of paracellular cation selectivity and functionality. Mice lacking both claudin-10 and -16 in the thick ascending limb recruited downstream compensatory mechanisms and showed hypertrophic distal convoluted tubules with changes in gene expression and phosphorylation of ion transporters in this segment, presumably triggered by the mild decrease in serum potassium. Thus, severe individual phenotypes in claudin-10 and claudin-16 knockout mice are corrected by the additional deletion of the other claudin.

Keywords: calcium; claudin; magnesium; paracellular pathway; thick ascending limb; tight junction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Claudins / deficiency*
  • Claudins / genetics
  • Disease Models, Animal
  • Gene Deletion
  • Genetic Predisposition to Disease
  • Hypercalciuria / genetics
  • Hypercalciuria / metabolism
  • Hypercalciuria / physiopathology
  • Hypercalciuria / prevention & control*
  • Kidney Tubules, Distal / metabolism*
  • Kidney Tubules, Distal / pathology
  • Kidney Tubules, Distal / physiopathology
  • Loop of Henle / metabolism*
  • Loop of Henle / pathology
  • Loop of Henle / physiopathology
  • Magnesium / metabolism
  • Magnesium Deficiency / genetics
  • Magnesium Deficiency / metabolism
  • Magnesium Deficiency / physiopathology
  • Magnesium Deficiency / prevention & control*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nephrocalcinosis / genetics
  • Nephrocalcinosis / metabolism
  • Nephrocalcinosis / physiopathology
  • Nephrocalcinosis / prevention & control
  • Phenotype
  • Sodium / metabolism


  • Claudins
  • claudin 10
  • claudin 16
  • Sodium
  • Magnesium
  • Calcium