Control of renal calcium permeability via a tight junctional claudin switch

Tight junctions seal the paracellular space between epithelial cells, with their claudin (CLDN) composition dictating epithelial permeability properties. In kidney thick ascending limbs, calcium is reabsorbed paracellularly through a meshwork of CLDN16 and CLDN19 polymers. CLDN14 is strongly upregulated by high blood calcium, restricts this paracellular calcium flux, and is linked to kidney stone disease. How CLDN14 controls paracellular calcium flux and structurally incorporates into this complex junction is unknown. Using confocal and super-resolution microscopy, we show that CLDN14 preferentially associates with CLDN19, thereby gradually replacing CLDN16 in the CLDN19 copolymer in vitro and in mice in vivo. The claudin switch depends on CLDN14 polymerization and occurs on a timescale of days via a pathway independent of dynamin-mediated endocytosis. Our findings reveal a mechanism of tight junction regulation, demonstrating how dynamic claudin remodeling within this complex structure controls renal calcium excretion and contributes to kidney stone pathogenesis.