title: Claudin-14 regulates renal Ca⁺⁺ transport in response to CaSR signalling via a novel microRNA pathway.
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.
authors.affiliation: Department of Internal Medicine, Washington University Renal Division, Washington University, St Louis, MO, USA.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Gong
authors.forename: Vijayaram
authors.initials: V
authors.lastname: Renigunta
authors.forename: Nina
authors.initials: N
authors.lastname: Himmerkus
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Zhang
authors.forename: Aparna
authors.initials: A
authors.lastname: Renigunta
authors.forename: Markus
authors.initials: M
authors.lastname: Bleich
authors.forename: Jianghui
authors.initials: J
authors.lastname: Hou
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D057167:Claudins / Q000378:metabolism*; D007668:Kidney / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*
chemical_list: D057167:Claudins; D035683:MicroRNAs; D044169:Receptors, Calcium-Sensing; D002118:Calcium; C422064:claudin 14