Claudin-10a Deficiency Shifts Proximal Tubular Cl-Permeability to Cation Selectivity viaClaudin-2 Redistribution

Claudin-10 is a tight junction protein expressed along the nephron. The claudin-10a isoform is a paracellular anion channel; claudin-10b facilitates paracellular Na+transport in the thick ascending limb. Mutations in the CLDN10gene that affect either claudin-10b or both isoforms cause HELIX syndrome. This study demonstrates that claudin-10a is essential for paracellular Cl-transport in the proximal tubule. In mice lacking claudin-10a, additional cation-selective claudin-2 incorporates into proximal tubule tight junctions. This turns paracellular anion into cation preference, with renal retention of calcium and magnesium and hypermagnesemia. Loss of anion permeability triggers compensation measures within the proximal tubule and in more distal parts of the nephron. Data from the claudin-10a?deficient mouse suggest mutations affecting both isoforms may result in a more severe electrolyte imbalance in HELIX syndrome.