{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nClaudin‐14 is a critical component of epithelial tight junctions in the inner ear where it is expressed in hair cells and their associated supporting cells. It forms a cation‐restrictive barrier that maintains the distinct ionic environment in the endolymph, essential for normal auditory function. Loss of claudin‐14 leads to rapid degeneration of outer hair cells, a reduction in presynaptic ribbon synapses, and the subsequent regression of auditory nerve processes, thereby contributing to sensorineural deafness. Alterations in endolymph ion concentrations observed in claudin‐14 knockout models further underscore its importance in inner ear ion homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the kidney, claudin‐14 localizes predominantly to the thick ascending limb (TAL) of Henle’s loop where it functions as a negative regulator of paracellular cation permeability. By physically interacting with claudin‐16 and claudin‐19, claudin‐14 modulates the reabsorption of calcium and magnesium. Its expression is tightly controlled by extracellular calcium levels acting through the Ca²⁺‐sensing receptor, with downstream regulation mediated by microRNAs (miR‑9 and miR‑374), NFATc1, and epigenetic mechanisms. Pharmacologic interventions such as histone deacetylase inhibitors further influence claudin‐14 expression, thereby altering renal calcium excretion and demonstrating its pivotal role in systemic calcium homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional investigations have explored claudin‐14 in the context of inter‐claudin interactions and vascular integrity. Studies using double knockout models with claudin‑11 indicate that, although each claudin independently contributes to epithelial barrier properties, there is little functional cooperation under normal physiological conditions. In contrast, partial loss of claudin‐14—as seen in heterozygous settings—can disrupt endothelial cell–cell junctions, alter laminin distribution in the basement membrane, increase vascular permeability in tumors, and enhance endothelial proliferation. These findings suggest that claudin‑14 may have context‐dependent roles beyond classical epithelial barriers, particularly in regulating angiogenesis and maintaining vascular integrity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging evidence also implicates claudin‐14 in the integrity of other epithelial barriers. In the urinary bladder, for example, reduced claudin‐14 expression in the setting of type 2 diabetes correlates with lower intracellular calcium levels, leading to impaired cell migration and a compromised barrier against pathogens. This novel link between extracellular calcium, claudin‐14 expression, and epithelial cohesion highlights potential therapeutic avenues for mitigating infection risks in diabetic patients."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Tamar Ben-Yosef, Inna A Belyantseva, Thomas L Saunders, et al. 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