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

Gong, Yongfeng, Renigunta, Vijayaram, Himmerkus, Nina, Zhang, Jiaqi, Renigunta, Aparna, Bleich, Markus and Hou, Jianghui (2012) Claudin-14 regulates renal Ca++transport in response to CaSR signalling via a novel microRNA pathway The EMBO Journal, 31 (8). pp. 1999-2012. DOI 10.1038/emboj.2012.49.

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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

Document Type: Article
Research affiliation: Kiel University
Kiel University > Kiel Marine Science
OceanRep > The Future Ocean - Cluster of Excellence
Refereed: Yes
DOI etc.: 10.1038/emboj.2012.49
ISSN: 02614189
Projects: Future Ocean
Date Deposited: 08 Mar 2017 10:49
Last Modified: 23 Mar 2017 14:43
URI: http://eprints.uni-kiel.de/id/eprint/36842

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