An epithelial morphogenetic program for maximal urine concentration

Mammals achieve the highest urine concentrations of any vertebrate, a feat that hinges on generating steep osmotic gradients within the renal medulla. Interestingly, the region with the highest osmolality, the inner medulla, is unique to mammals. Among the nephron's segments, the ascending thin limb (aTL) is the sole element exclusive to this zone and is thought to mediate passive salt reabsorption. However, the architecture and functional impact of the aTL have remained obscure. Here we uncover an unexpected morphogenetic program in the aTL, characterized by extensive apical-junctional interdigitations that greatly increase cell-to-cell contact area. Integrating single-nucleus transcriptomics with high-resolution imaging, we identify claudin-10b, a tight junction protein and paracellular cation pore, as a central driver of this architecture. Inducible deletion of claudin-10b specifically in the aTL abolishes membrane interdigitations and markedly reduces urine-concentrating ability, thereby establishing a direct link between segment-specific epithelial morphology and whole-organ function. Claudin-10b proves necessary for interdigitation formation, acting through transcellular adhesion and interaction with the tight-junction scaffold ZO1. These findings offer definitive evidence that the inner medulla and aTL are essential for maximal urinary concentration, while revealing a non-canonical, morphogenetic role for claudin-10b.