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 language | English |
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Pages (from-to) | 1999-2012 |
Number of pages | 14 |
Journal | EMBO Journal |
Volume | 31 |
Issue number | 8 |
DOIs | |
State | Published - Apr 18 2012 |
Keywords
- bone mineral loss
- hypercalciuria
- kidney stone
- tight junction