Salt and acid-base metabolism in claudin-16 knockdown mice: Impact for the pathophysiology of FHHNC patients

Nina Himmerkus, Qixian Shan, Boeren Goerke, Jianghui Hou, Daniel A. Goodenough, Markus Bleich

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35 Scopus citations


Claudin-16 is defective in familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). Claudin-16 knockdown (CLDN16 KD) mice show reduced cation selectivity in the thick ascending limb. The defect leads to a collapse of the lumen-positive diffusion voltage, which drives Ca2+ and Mg2+ absorption. Because of the reduced tight junction permeability ratio for Na+ over Cl-, we proposed a backleak of NaCl into the lumen. Systemic analysis had revealed lower blood pressure and a moderately increased plasma aldosterone concentration. In this study, we measured the amiloride-sensitive equivalent short-circuit current in isolated, perfused collecting ducts and found it increased by fivefold in CLDN16 KD mice compared with wild-type (WT) mice. Amiloride treatment unmasked renal Na + loss in the thick ascending limb of the nephron. Under amiloride treatment, CLDN16 KD mice developed hyponatremia and the renal fractional excretion of Na+ was twofold higher in CLDN16 KD compared with WT mice. The loss of claudin-16 also resulted in increased urinary flow, reduced HCO3- excretion, and lower urine pH. We conclude that perturbation in salt and acid-base metabolism in CLDN16 KD mice has its origin in the defective cation permselectivity of the thick ascending limb of the nephron. This study has contributed to the still incomplete understanding of the symptoms of FHHNC patients.

Original languageEnglish
Pages (from-to)F1641-F1647
JournalAmerican Journal of Physiology - Renal Physiology
Issue number6
StatePublished - Dec 2008


  • Amiloride
  • Calcium
  • Magnesium
  • Paracellular ion transport
  • Thick ascending limb

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