Tonicity drives maturation of the collecting ducts in the mammalian kidney

As the kidney matures, the osmolality in the renal medulla increases for urine concentration, but how this extreme environment conversely contributes to kidney maturation is unclear. Here we show that high tonicity, i.e. high salt concentration, promotes the maturation of mouse embryonic kidneys and human kidney organoids.

Exposure of mouse embryonic collecting ducts (CDs) to high tonicity induces morphological changes in the epithelia, upregulates maturation-associated genes, and confers responsiveness to antidiuretic hormone, which mainly depend on the transcription factor NFAT5 (nuclear factor of activated T cells 5). Based on these findings, we have established a robust maturation protocol for human CD organoids that allows recapitulation of disease states caused not only by NFAT5 deletion, but also by a missense mutation of the antidiuretic hormone receptor reported to cause congenital nephrogenic diabetes insipidus.