TY - JOUR
T1 - Claudin-14 regulates renal Ca ++ transport in response to CaSR signalling via a novel microRNA pathway
AU - Gong, Yongfeng
AU - Renigunta, Vijayaram
AU - Himmerkus, Nina
AU - Zhang, Jiaqi
AU - Renigunta, Aparna
AU - Bleich, Markus
AU - Hou, Jianghui
PY - 2012/4/18
Y1 - 2012/4/18
N2 - 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.
AB - 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.
KW - bone mineral loss
KW - hypercalciuria
KW - kidney stone
KW - tight junction
UR - http://www.scopus.com/inward/record.url?scp=84862804787&partnerID=8YFLogxK
U2 - 10.1038/emboj.2012.49
DO - 10.1038/emboj.2012.49
M3 - Article
C2 - 22373575
AN - SCOPUS:84862804787
VL - 31
SP - 1999
EP - 2012
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
IS - 8
ER -