Claudin-16 and claudin-19 interact and form a cation-selective tight junction complex
Jianghui Hou, … , Siegfried Waldegger, Daniel A. Goodenough
Jianghui Hou, … , Siegfried Waldegger, Daniel A. Goodenough
Published January 10, 2008
Citation Information: J Clin Invest. 2008;118(2):619-628. https://doi.org/10.1172/JCI33970.
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Research Article Nephrology

Claudin-16 and claudin-19 interact and form a cation-selective tight junction complex

Abstract

Tight junctions (TJs) play a key role in mediating paracellular ion reabsorption in the kidney. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an inherited disorder caused by mutations in the genes encoding the TJ proteins claudin-16 (CLDN16) and CLDN19; however, the mechanisms underlying the roles of these claudins in mediating paracellular ion reabsorption in the kidney are not understood. Here we showed that in pig kidney epithelial cells, CLDN19 functioned as a Cl– blocker, whereas CLDN16 functioned as a Na+ channel. Mutant forms of CLDN19 that are associated with FHHNC were unable to block Cl– permeation. Coexpression of CLDN16 and CLDN19 generated cation selectivity of the TJ in a synergistic manner, and CLDN16 and CLDN19 were observed to interact using several criteria. In addition, disruption of this interaction by introduction of FHHNC-causing mutant forms of either CLDN16 or CLDN19 abolished their synergistic effect. Our data show that CLDN16 interacts with CLDN19 and that their association confers a TJ with cation selectivity, suggesting a mechanism for the role of mutant forms of CLDN16 and CLDN19 in the development of FHHNC.

Authors

Jianghui Hou, Aparna Renigunta, Martin Konrad, Antonio S. Gomes, Eveline E. Schneeberger, David L. Paul, Siegfried Waldegger, Daniel A. Goodenough

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Figure 6

Function of TJ and mechanism of Mg2+ reabsorption.

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Function of TJ and mechanism of Mg2+ reabsorption. In TA...
In TAL, NaCl reabsorption is mediated through Na+K+Cl–-cotransporter type 2 (NKCC2) in the apical membrane. On the basolateral side, Na/K-ATPase provides the energy source and also allows Na+ to exit the cell in exchange for K+ entry. K+ is secreted to the lumen side via the renal outer medullary K+ channel (ROMK). Cl– exits the cell via the Cl– channel (CLC). Continuous NaCl reabsorption along TAL results in gradual tubular fluid dilution and the development of a transepithelial NaCl concentration gradient (from peritubular space, 140 mM, down to lumen, 30 mM). As the epithelial cells in TAL are joined by cation-selective TJs, the NaCl concentration gradient results in a lumen-positive transepithelial diffusion potential. This positive potential drives the reabsorption of Mg2+ and Ca2+ through the TJ (known as the paracellular pathway). CLDN16 and CLDN19 interact in TJs and contribute to the cation selectivity of TJs.