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

EMBO J. 2012 Apr 18;31(8):1999-2012. doi: 10.1038/emboj.2012.49. Epub 2012 Feb 28.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Claudins / metabolism*
  • Kidney / physiology*
  • Mice
  • Mice, Knockout
  • MicroRNAs / metabolism*
  • Receptors, Calcium-Sensing / metabolism*


  • Claudins
  • MicroRNAs
  • Receptors, Calcium-Sensing
  • Calcium
  • claudin 14