Claudin-15 forms a water channel through the tight junction with distinct function compared to claudin-2

Abstract

Aim: Claudin-15 is mainly expressed in the small intestine and indirectly involved in glucose absorption. Similar to claudin-2 and -10b, claudin-15 is known to form a paracellular channel for small cations. Claudin-2, but not claudin-10b, also forms water channels. Here we experimentally tested whether claudin-15 also mediates water transport and if yes, whether water transport is Na⁺ -coupled, as seen for claudin-2.

Methods: MDCK C7 cells were stably transfected with claudin-15. Ion and water permeability were investigated in confluent monolayers of control and claudin-15-expressing cells. Water flux was induced by an osmotic or ionic gradient.

Results: Expression of claudin-15 in MDCK cells strongly increased cation permeability. The permeability ratios for monovalent cations indicated a passage of partially hydrated ions through the claudin-15 pore. Accordingly, its pore diameter was determined to be larger than that of claudin-2 and claudin-10b. Mannitol-induced water flux was elevated in claudin-15-expressing cells compared to control cells. In contrast to the Na⁺ -coupled water flux of claudin-2 channels, claudin-15-mediated water flux was inhibited by Na⁺ flux. Consequently, water flux was increased in Na⁺ -free solution. Likewise, Na⁺ flux was decreased after induction of water flux through claudin-15.

Conclusion: Claudin-15, similar to claudin-2, forms a paracellular cation and water channel. In functional contrast to claudin-2, water and Na⁺ fluxes through claudin-15 inhibit each other. Claudin-15 allows Na⁺ to retain part of its hydration shell within the pore. This then reduces the simultaneous passage of additional water through the pore.

Keywords: claudin-15 pore diameter; paracellular ion permeability; paracellular water permeability.