Insights into driving forces and paracellular permeability from claudin-16 knockdown mouse

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

Research output: Chapter in Book/Report/Conference proceedingChapter

21 Scopus citations

Abstract

Tight junction (TJ) properties are determined by membrane protein complexes of neighboring cells that form both a barrier and a selective pathway for paracellular substrate transport. Our previous work supports the view that paracellular permeability changes in the thick ascending limb (TAL) may underlie the mechanism for familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), a rare autosomal recessive disease linked to mutations in claudin-16 (CLDN16) and claudin-19 (CLDN19). CLDN16 knockdown (KD) mice are lacking CLDN16 expression by transgenic RNA interference. We observed that the transport defect for Mg2+ and Ca2+ in this animal model is caused by a loss of paracellular cation selectivity. The permeability ratio for Na+ over Cl- in KD mice was lower by a factor of two without a change in paracellular conductance, compared to wild type (WT). This resulted in a collapse of the transepithelial voltage, which is the driving force for Mg2+ and Ca2+ absorption in TAL. Since CLDN16 KD mice revealed lower blood pressure and an increased aldosterone plasma concentration, we hypothesize that the reduction in paracellular selectivity could allow backflow of Na+ and Cl- into the lumen of the TAL, thus enhancing the distal NaCl load and challenging the organism with a latent NaCl loss.

Original languageEnglish
Title of host publicationMolecular Structure and Function of the Tight Junction From Basic Mechanisms to Clinical Manifestations
PublisherBlackwell Publishing Inc.
Pages148-151
Number of pages4
ISBN (Print)9781573317498
DOIs
StatePublished - May 2009
Externally publishedYes

Publication series

NameAnnals of the New York Academy of Sciences
Volume1165
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632

Keywords

  • Electrolyte metabolism
  • Electropyhsiology
  • Tight junction

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    Shan, Q., Himmerkus, N., Hou, J., Goodenough, D. A., & Bleich, M. (2009). Insights into driving forces and paracellular permeability from claudin-16 knockdown mouse. In Molecular Structure and Function of the Tight Junction From Basic Mechanisms to Clinical Manifestations (pp. 148-151). (Annals of the New York Academy of Sciences; Vol. 1165). Blackwell Publishing Inc.. https://doi.org/10.1111/j.1749-6632.2009.04041.x