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During the congress, E-Posters will be accessible to all participants on the congress website 24/7, as well as in the E-poster stations in the congress center.
Preparing your E-Poster
Please review the E-Poster format requirements carefully when preparing your E-Poster. Should your E-Poster not meet the mentioned requirements, it may not be displayed as described above.
E-Poster Submission Deadline
Please prepare and upload your E-Poster no later than March 14, 2026 11.59PM CET. After this date, you will no longer be able to prepare and upload your E-poster and it will not be displayed and accessible on the congress website.
Please follow the instructions below to input your abstract title.
Abstract titles should be brief and reflect the content of the abstract.
ARPKD leads to severe renal cysts and progressive kidney dysfunction, with no approved treatments. We recently developed kidney organoid-on-chip models that mimic patients’ distal-nephron cysts, identifying RAC1/c-FOS as potential therapeutic targets for ARPKD patients. However, critical questions remain regarding RAC1’s precise role in cyst formation, cyst origins, and underlying molecular mechanisms. In this study, we aim to elucidate the process leading to RAC1 activation during cyst formation in ARPKD using a fluidic culture system that reproduces disease pathogenesis. By analyzing reconstructed cysts in detail, we further investigate their cellular origin and molecular pathways. These insights are expected to deepen our understanding of ARPKD cystogenesis and pave the way for novel therapeutic strategies.
We analyzed RNA-seq data from human kidney organoids derived from pluripotent stem cells with heterozygous or homozygous PKHD1 mutations, cultured using an organoid-on-chip system that models cyst formation in CDH1⁺ distal nephrons, resembling ARPKD pathology. Differential gene expression analyses were conducted to compare PKHD1+/– and PKHD1–/– organoids. To validate these findings, we used an integrated approach combining an enhanced microfluidic perfusion system, transgenic mouse mice, and human kidney samples.
We identified 27 RAC1 partner genes with significantly altered expression in PKHD1-/- organoids compared to controls, with most being downregulated. Among these, SPTAN1 was the only partner gene associated with cystic biology and distal nephron localization. Immunostaining of kidney organoids mirrored the expression pattern of SPTAN1 in the human kidney, demonstrating reduced SPTAN1 expression in PKHD1-/- ARPKD organoids. Moreover, SPTAN1-mutant kidney organoids exhibited distal-nephron cysts, and elevated RAC1/c-FOS expression, consistent with ARPKD patients. Consistently, Sptan1+/- mice exhibited enlarged kidneys and the dilation of distal-nephron. Transcriptomics and live imaging revealed altered calcium signaling and increased intracellular calcium. Single-cell RNA-seq identified SLC8A1, a sodium/calcium exchanger, as a marker distinguishing distal/connecting tubules from collecting ducts in human kidneys, predominantly expressed in cystic epithelia in organoids and human ARPKD kidneys. Furthermore, Restoring SPTAN1 in PKHD1-/- organoids via CRISPR activation alleviated cystic phenotypes, normalized intracellular calcium, and reduced RAC1/c-FOS expression.
Through a multifaceted approach, we identified SPTAN1 as a key regulator of cystic pathology in ARPKD. These findings establish SPTAN1 as a central regulator of ARPKD pathogenesis and highlight epigenome editing as a potential therapeutic strategy, paving the way for the translation of findings from basic research into clinical practice.
This abstract has been presented at the American Society of Nephrology Kidney Week 2025, and re-submission is permitted by the organizers.
