Low-Salt Diet Induces Claudin-3 Expression and Drives Adaptive Changes in Collecting Duct of Claudin-3-Deficient Mice.

Abstract

Renal sodium reabsorption occurs through both transcellular and paracellular pathways. Tight junction proteins play a key role in mediating paracellular transport. The collecting duct is critical for the fine tuning of sodium balance and is highly responsive to changes in dietary salt intake. This study aimed to determine whether a low-sodium diet modulates paracellular sodium permeability by regulating the expression or localization of claudin-3, a major tight junction protein in the collecting duct. Wild-type and claudin-3 knockout male mice were fed low (0.01%) or normal (0.18%) sodium diets for 7 days, with or without treatment with spironolactone, a mineralocorticoid receptor antagonist. The expression of tight junction proteins was analyzed by immunoblotting and immunofluorescence. Functional effects of claudin-3 on ion permeability were evaluated in cultured mouse collecting duct principal cells using chamber recordings after claudin-3 overexpression or gene silencing. Low-sodium diet increases claudin-3 expression in mouse kidneys. In cultured cells, aldosterone enhanced claudin-3 abundance and its plasma membrane localization. Claudin-3 overexpression reduced, while its silencing increased paracellular permeability to sodium and chloride. Claudin-3 knockout mice on a low-sodium diet compensated by upregulating epithelial sodium channel subunits, claudin-4, claudin-8, and claudin-10. This adaptive response persisted under mineralocorticoid receptor blockade. Our findings demonstrate that aldosterone strengthens the paracellular sodium barrier in the collecting duct by inducing claudin-3. In the absence of claudin-3, compensatory regulation of other claudins and sodium transporters preserves sodium homeostasis under low-salt conditions, thus revealing adaptive mechanisms in renal sodium handling.