Kidney Week

Abstract: TH-OR056

Spatial Transcriptomics Reveal Progressive Tubular-to-Cyst Transitions and Conserved Transcription Factor Networks in Mouse and Human ADPKD

Session Information

• Genetic Diseases with a Focus on ADPKD Mechanisms, Models, and Medicines
  October 22, 2026 | Location: Mile High Ballroom 4D, Convention Center
  Abstract Time: 04:40 PM - 04:50 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)

Authors

• Flournoy, Torrey, The University of Alabama at Birmingham, Birmingham, Alabama, United States

Torrey Flournoy, PhD

• Hough, Kenneth, Cytogence, Birmingham, Alabama, United States

Kenneth Hough, PhD

• Moran-Reyna, Aida, The University of Alabama at Birmingham, Birmingham, Alabama, United States

Aida Moran-Reyna, MSc

• Hallit, Emily, The University of Alabama at Birmingham, Birmingham, Alabama, United States

Emily Hallit

• Sedaka, Randee, The University of Alabama at Birmingham, Birmingham, Alabama, United States

Randee Sedaka, PhD

• Song, Cheng "Jack", The University of Alabama at Birmingham, Birmingham, Alabama, United States

Cheng "Jack" Song, PhD

• Saigusa, Takamitsu, The University of Alabama at Birmingham, Birmingham, Alabama, United States

Takamitsu Saigusa, MD

Background

Loss of PKD1 drives cystogenesis in autosomal dominant polycystic kidney disease (ADPKD), yet the transcriptional programs driving the tubule-to-cyst transition remain unclear. We applied NanoString GeoMx® Digital Spatial Profiling (DSP) to map gene expression changes specifically in the tubular epithelia and identify regulatory transcription factor (TF) networks in an ADPKD mouse model, followed by cross-species validation in human PKD organoids.

Methods

Adult Pkd1^flox/flox CAGG-CreER2 (Pkd1KO) mouse kidney sections were stained for proximal (AQP1) and distal tubules (NCC) to select regions of interest (ROIs): normal epithelia (Flox), mildly dilated cysts, transitional zones (cyst periphery) and severe cysts. The GeoMx Whole Transcriptome Atlas captured spatially resolved expression. Differential expression (DE; Pkd1KO vs. Flox) was followed by stage-trajectory modeling (Spearman correlation with progression score and ANOVA across the four stages) to classify progression-associated genes by temporal pattern. ChEA3 TF enrichment of DE genes identified candidate regulators driving pro-cystic signatures, which were cross-referenced with human PKD1 vs. normal kidney organoid RNA-seq data to identify conserved cyst-promoting genes.

Results

Progressive upregulation of DE genes occurred across stages (normal < mild cyst < transitional < severe cyst). Transitional ROIs exhibited hybrid molecular signatures bridging normal tubular and cystic states. TFs regulating cyst progression-associated genes were prioritized by ChEA3 mean rank and disease-severity correlation (Spearman r ≥ 0.6 with progression score). Cross-species validation identified concordant genes upregulated in both mice and human organoids (i.e. ANXA3, CCN1, CD74, CDKN1A, CRYAB, GLIS2). Protein-protein interaction network analysis revealed 7 interconnected modules (immune/antigen presentation, cell adhesion/signaling, chaperone/stress response, cell cycle regulation) with hubs including B2M and CD74.

Conclusion

Spatial transcriptomics identified dynamic molecular transitions during cystogenesis and prioritized pro-cystic TF candidates whose downstream target signatures are conserved between mouse and human PKD. Transitional epithelial states represent a potential therapeutic window, and prioritized TFs may offer novel targets to slow cystogenesis in ADPKD.

Acknowledgment

This work was supported by the resources and staff at the University of Minnesota Univeristy Imaging Center (SCR_020997) and Genomics Center Core Facility (SCR_012413).

Funding

• NIDDK Support