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.
Schizophrenia is a neurodevelopmental disorder that affects up to 1% of the general population. Various genes show associations with schizophrenia and a very weak nominal association with the tight junction protein, claudin-5, has previously been identified. Claudin-5 is expressed in endothelial cells forming part of the blood-brain barrier (BBB). Furthermore, schizophrenia occurs in 30% of individuals with 22q11 deletion syndrome (22q11DS), a population who are haploinsufficient for the claudin-5 gene. Here, we show that a variant in the claudin-5 gene is weakly associated with schizophrenia in 22q11DS, leading to 75% less claudin-5 being expressed in endothelial cells. We also show that targeted adeno-associated virus-mediated suppression of claudin-5 in the mouse brain results in localized BBB disruption and behavioural changes. Using an inducible 'knockdown' mouse model, we further link claudin-5 suppression with psychosis through a distinct behavioural phenotype showing impairments in learning and memory, anxiety-like behaviour and sensorimotor gating. In addition, these animals develop seizures and die after 3-4 weeks of claudin-5 suppression, reinforcing the crucial role of claudin-5 in normal neurological function. Finally, we show that anti-psychotic medications dose-dependently increase claudin-5 expression in vitro and in vivo while aberrant, discontinuous expression of claudin − 5 in the brains of schizophrenic patients post mortem was observed compared to age-matched controls. Together, these data suggest that BBB disruption may be a modifying factor in the development of schizophrenia and that drugs directly targeting the BBB may offer new therapeutic opportunities for treating this disorder.
Pathologic dysregulation of extracellular calcium metabolism is difficult to correct. The extracellular Ca ++ -sensing receptor (CaSR), a G protein-coupled receptor that regulates renal Ca ++ handling through changes in paracellular channel permeability in the thick ascending limb, has emerged as an effective pharmacological candidate for managing calcium metabolism. However, manipulation of CaSR at the systemic level causes promiscuous effects in the parathyroid glands, kidneys, and other tissues, and the mechanisms by which CaSR regulates paracellular transport in the kidney remain unknown. Here, we describe a CaSR-NFATc1-microRNAclaudin-14 signaling pathway in the kidney that underlies paracellular Ca ++ reabsorption through the tight junction. With CaSR-specific pharmacological reagents, we show that the in vivo gene expression of claudin-14 is regulated through a transcriptional mechanism mediated by NFATc1-microRNA and associated chromatin remodeling. Transgenic knockout and overexpression approaches showed that claudin-14 is required for CaSR-regulated renal Ca ++ metabolism. Together, our results define an important signaling cascade that, when dysregulated, may mediate Ca ++ imbalance through changes in tight junction permeability.
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