Claudin-7 Modulates Cl− and Na+ Homeostasis and WNK4 Expression in Renal Collecting Duct Cells

Claudin-7 knockout (CLDN7−/−) mice display renal salt wasting and dehydrationphenotypes. To address the role of CLDN7 in kidneys, we established collecting duct (CD) celllines from CLDN7+/+ and CLDN7−/− mouse kidneys. We found that deletion of CLDN7 increasedthe transepithelial resistance (TER) and decreased the paracellular permeability for Cl− and Na+ inCLDN7−/− CD cells. Inhibition of transcellular Cl− and Na+ channels has no significant effect on TERor dilution potentials. Current-voltage curves were linear in both CLDN7+/+ and CLDN7−/− CD cells,indicating that the ion flux was through the paracellular pathway. The impairment of Cl− and Na+permeability phenotype can be rescued by CLDN7 re-expression. We also found that WNK4 (itsmutations lead to hypertension) expression, but not WNK1, was significantly increased in CLDN7−/−CD cell lines as well as in primary CLDN7−/− CD cells, suggesting that the expression of WNK4was modulated by CLDN7. In addition, deletion of CLDN7 upregulated the expression level of theapical epithelial sodium channel (ENaC), indicating a potential cross-talk between paracellular andtranscellular transport systems. This study demonstrates that CLDN7 plays an important role insalt balance in renal CD cells and modulating WNK4 and ENaC expression levels that are vital incontrolling salt-sensitive hypertension