High tonicity drives mammalian kidney maturation, allowing human collecting duct organoids to acquire vasopressin responsiveness and model congenital nephrogenic diabetes insipidus.
Urinary biomarkers of tubular stress and congestion (L-FABP, NGAL, tAM) do not significantly correlate with diuretic response in patients hospitalized for acute heart failure.
tonicity.This maturation process was mainly dependent on NFAT5.In scRNA-seq analysis, mouse CD organoids cultured at high tonicity in the presence of vasopressin and aldosterone overlapped with postnatal day 7 medullary CDs with high expression levels of marker genes such as Aqp2 and Slc14a2.Additionally, we have established a maturation protocol for human CD organoids.These organoids also underwent morphological and transcriptional maturation and acquired vasopressin responsiveness at high tonicity.scRNA-seq analysis revealed that the mature CD organoids exhibited comparable expression levels of maturation markers to those of adult CDs.Finally, the mature CD organoids induced from iPSCs harboring a causative AVPR2 mutation of congenital NDI lost vasopressin responsiveness.In contrast, the healthy organoids responded to vasopressin with clear AQP2 expression in the apical membrane.Conclusion: High tonicity is a driving force not only for urine concentration, but also for mammalian kidney maturation.Our mature CD organoids reached a postnatal stage, and potentially an adult stage.Our study uncovers a novel principle of kidney maturation triggered by environmental cues and offers a promising approach to maximize the potential of kidney organoids for future therapies.I have no potential conflict of interest to disclose.I did not use generative AI and AI-assisted technologies in the writing process.
Hirai et al. (2026) studied this question. High tonicity drives mammalian kidney maturation, allowing human collecting duct organoids to acquire vasopressin responsiveness and model congenital nephrogenic diabetes insipidus.