Claudin-3 is expressed at the macula densa and is associated with altered glomerular filtration in claudin-3 knockout mice.

Claudin-3 is a tight junction protein expressed in the distal nephron, notably in the thick ascending limb of Henle's loop and the distal convoluted tubule, where it acts as an aldosterone-regulated paracellular barrier to sodium and chloride transport. Here, we demonstrate that claudin-3 knockout (KO) mice exhibit an unexpected diet-dependent alteration in glomerular filtration rate (GFR): under a normal sodium (NS) diet, GFR decreases significantly, whereas under a low sodium (LS) diet, GFR increases paradoxically compared with wild-type controls. To identify the underlying mechanism, we examined claudin-3 expression in the macula densa, the specialized epithelial structure located at the junction between the thick ascending limb and the distal convoluted tubule that governs tubuloglomerular feedback (TGF). Immunofluorescence analysis revealed that claudin-3 colocalizes with neuronal nitric oxide synthase (nNOS) and the Na+-K+-2Cl- cotransporter (NKCC2) in a distinct cluster of cells characterized by densely packed nuclei, positioned in direct contact with the glomerulus and immediately adjacent to an NCC-positive distal convoluted tubule, while remaining itself NCC-negative. Notably, within the tubule containing the macula densa, nNOS expression was strictly confined to macula densa cells, clearly distinguishing them from the surrounding tubular epithelium. These results identify claudin-3 as a previously unrecognized component of macula densa biology and suggest a role for claudin-3 in the control of GFR possibly via the tubuloglomerular feedback.