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| Item Type: | Preprint |
|---|---|
| Title: | Cyst-type epithelial heterogeneity shapes therapeutic responsiveness in ADPKD |
| Creators: |
Roeles, Johannes, Giesler, Axel, Schmitz, Jessica, König, Johannes, Friedersdorff, Frank, Busch, Jonas, Greite, Robert, Krappitz, Matteus, Layne, Isabel A., Köttgen, Michael  ORCID: https://orcid.org/0000-0003-2406-5039, Kuehn, E. Wolfgang, Schmid, Jessica, Schmidt, Katharina, Hoeft, Konrad, Kramann, Rafael, Eckardt, Kai-Uwe, Kocks, Christine ORCID: https://orcid.org/0000-0003-1749-3334, Bräsen, Jan H., Halbritter, Jan, Schmitt, Roland, Härteis, Silke, Hopp, Katharina, Schmidt-Ott, Kai M. ORCID: https://orcid.org/0000-0002-7700-7142 and Hinze, Christian ORCID: https://orcid.org/0000-0003-2526-1621
|
| Abstract: | Autosomal dominant polycystic kidney disease (ADPKD) exhibits substantial interpatient variability in disease course and therapeutic response, but the cellular basis for this variability remains poorly understood. Here, we combine single-nucleus RNA sequencing of human cyst epithelia with machine learning–based histological analysis of >1,800 cysts to resolve three epithelial cyst types—proximal tubule–like, collecting duct–like, and mixed. These cyst types display distinct injury states, metabolic programs, and stromal microenvironments, including a mixed-cyst niche enriched for CCL2-associated inflammatory signaling. Expression of key therapeutic targets was highly cell-type specific with CFTR enriched in proximal-like epithelia, whereas AVPR2 expression was confined to AQP2-positive collecting duct–like cells. Cyst-type composition varied widely across patients and in an orthologous mouse model (Pkd1(RC/RC)) in which the burden of AQP2-positive cysts correlated with responsiveness to tolvaptan. These findings identify cyst-type heterogeneity as a major determinant of molecular pathway activation and predictability of therapeutic response in ADPKD. |
| Keywords: | Animals, Mice |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2026.05.08.723838 |
| Date: | 12 May 2026 |
| Official Publication: | https://doi.org/10.64898/2026.05.08.723838 |
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