Claudin-4 forms paracellular chloride channel in the kidney and requires claudin-8 for tight junction localization

Jianghui Hou, Aparna Renigunta, Jing Yang, Siegfried Waldegger

Research output: Contribution to journalArticlepeer-review

147 Scopus citations


Tight junctions (TJs) play a key role in mediating paracellular ion reabsorption in the kidney. The paracellular pathway in the collecting duct of the kidney is a predominant route for transepithelial chloride reabsorption that determines the extracellular NaCl content and the blood pressure. However, the molecular mechanisms underlying the paracellular chloride reabsorption in the collecting duct are not understood. Here we showed that in mouse kidney collecting duct cells, claudin-4 functioned as a Cl- channel. A positively charged lysine residue at position 65 of claudin-4 was critical for its anion selectivity. Claudin-4 was observed to interact with claudin-8 using several criteria. In the collecting duct cells, the assembly of claudin-4 into TJ strands required its interaction with claudin-8. Depletion of claudin-8 resulted in the loss of paracellular chloride conductance, through a mechanism involving its recruitment of claudin-4 during TJ assembly. Together, our data show that claudin-4 interacts with claudin-8 and that their association is required for the anion-selective paracellular pathway in the collecting duct, suggesting a mechanism for coupling chloride reabsorption with sodium reabsorption in the collecting duct.

Original languageEnglish
Pages (from-to)18010-18015
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number42
StatePublished - Oct 19 2010


  • Blood pressure
  • Chloride shunt
  • Ion channel
  • Protein interaction
  • siRNA


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