Claudin-14 regulates renal Ca ++ transport in response to CaSR signalling via a novel microRNA pathway

Yongfeng Gong, Vijayaram Renigunta, Nina Himmerkus, Jiaqi Zhang, Aparna Renigunta, Markus Bleich, Jianghui Hou

Research output: Contribution to journalArticle

139 Scopus citations

Abstract

The paracellular claudin channel of the thick ascending limb (TAL) of Henle is critical for Ca ++ reabsorption in the kidney. Genome-wide association studies (GWASs) have identified claudin-14 associated with hypercalciuric nephrolithiasis. Here, we show that claudin-14 promoter activity and transcript are exclusively localized in the TAL. Under normal dietary condition, claudin-14 proteins are suppressed by two microRNA molecules (miR-9 and miR-374). Both microRNAs directly target the 3′-UTR of claudin-14 mRNA; induce its mRNA decay and translational repression in a synergistic manner. Through physical interaction, claudin-14 blocks the paracellular cation channel made of claudin-16 and -19, critical for Ca ++ reabsorption in the TAL. The transcript and protein levels of claudin-14 are upregulated by high Ca ++ diet, while downregulated by low Ca ++ diet. Claudin-14 knockout animals develop hypermagnesaemia, hypomagnesiuria, and hypocalciuria under high Ca ++ dietary condition. MiR-9 and miR-374 transcript levels are regulated by extracellular Ca ++ in a reciprocal manner as claudin-14. The Ca ++ sensing receptor (CaSR) acts upstream of the microRNA-claudin-14 axis. Together, these data have established a key regulatory role for claudin-14 in renal Ca ++ homeostasis.

Original languageEnglish
Pages (from-to)1999-2012
Number of pages14
JournalEMBO Journal
Volume31
Issue number8
DOIs
StatePublished - Apr 18 2012

Keywords

  • bone mineral loss
  • hypercalciuria
  • kidney stone
  • tight junction

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