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Combinatorial expression of claudins in the proximal renal tubule and its functional consequences.

The proximal renal tubule (PT) is characterized by a highly conductive paracellular pathway, which contributes to a significant amount of solute and water reabsorption by the kidney. Claudins are tight junction proteins that in part determine the paracellular permeability of epithelia. In this study, we determined the expression pattern of the major PT claudins. We found that claudin-2 and claudin-10 are co-expressed throughout the PT, whereas claudin-3 is co-expressed with claudin-2 predominantly in the proximal straight tubule. Additionally, claudin-2 and claudin-3 are expressed separately within mutually exclusive populations of descending thin limbs. We developed a novel double-inducible MDCK I cell model to characterize in vitrothe functional effect of co-expression of PT claudins. In keeping with previous studies, we found that claudin-2 alone primarily increased cation (Na+and Ca2+) permeability while claudin-10a alone increased anion (Cl-) permeability. Co-expression of claudin-2 and -10a together led to a weak physical interaction between the isoforms and the formation of a monolayer with high conductance but neutral charge selectivity. Claudin-3 expression had negligible effect on all measures of cell permeability, whether expressed alone or together with claudin-2. In cells co-expressing a claudin-2 mutant, S68C, together with claudin-10a, inhibition of cation permeability through the claudin-2 pore with a thiol-reactive pore blocker did not block anion permeation through claudin-10a. We conclude that claudins-2 and -10a form independent paracellular cation- and anion-selective channels that function in parallel.