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Claudin‐14 regulates renal Ca ++ transport in response to CaSR signalling via a novel microRNA pathway
Author(s) -
Gong Yongfeng,
Renigunta Vijayaram,
Himmerkus Nina,
Zhang Jiaqi,
Renigunta Aparna,
Bleich Markus,
Hou Jianghui
Publication year - 2012
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2012.49
Subject(s) - biology , microrna , signalling , microbiology and biotechnology , signal transduction , gene , genetics
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.