Purpose of review: Tight junctions formed by claudins regulate paracellular permeability to sodium, chloride, calcium, magnesium, and water along the nephron, thereby enabling energy-efficient reabsorption of glomerular filtrate that limits tubular oxygen consumption.

Recent findings: We review evidence from knockout models, cell lines, and single-cell analyses demonstrating highly segment-specific claudin functions along the nephron. In the proximal tubule, independent claudin-2 and claudin-10a pores mediate cation/water and anion permeability, respectively, and inducible claudin-2 deletion causes hypercalciuria and nephrocalcinosis. In the thick ascending limb, three functionally distinct cell populations express different claudin combinations, with claudin-10b driving paracellular Na+ permeability and claudin-16/19 mediating Ca2+ and Mg2+ reabsorption. In the aldosterone-sensitive distal nephron, coupling between ENaC-ɣ and claudin-8 links transcellular Na+ entry to the prevention of paracellular Na+ back-leak independently of aldosterone, whereas aldosterone transcriptionally upregulates claudin-3 and claudin-8. Claudin-3 deficiency triggers compensatory upregulation of ENaC and claudins-4/8/10 to preserve sodium balance. Claudin-4 is upregulated in nephrotic syndrome and promotes NaCl retention. These findings reveal paracellular pathway's critical role in metabolic efficiency and tubulopathy pathogenesis.

Summary: Claudins form segment-specific paracellular pathways that enable efficient ion and water reabsorption with low metabolic cost along the nephron. Mutations with loss of function of claudins cause tubulopathies with salt loss, hypomagnesemia, and/or nephrocalcinosis and kidney stones. Future studies using inducible and segment-specific models will be essential to identify strategies to restore paracellular transport in kidney disease.