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Kidney Week

Abstract: FR-PO575

Tumor-Associated Calcium Signal Transducer 2 (Tacstd2) Expression Is Increased in Early Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic

Authors

  • Smith, Abigail O., University of Massachusetts Chan Medical School, Worcester, Massachusetts, United States
  • Frantz, William Tyler, University of Massachusetts Chan Medical School, Worcester, Massachusetts, United States
  • Preval, Kenley M., University of Massachusetts Chan Medical School, Worcester, Massachusetts, United States
  • Edwards, Yvonne J., The University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, United States
  • Jonassen, Julie A., University of Massachusetts Chan Medical School, Worcester, Massachusetts, United States
  • Pazour, Gregory J., University of Massachusetts Chan Medical School, Worcester, Massachusetts, United States
Background

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by polycystin gene mutations, leading to kidney cysts. Cysts grow via abnormal epithelial proliferation and secretion. Despite known mutations and pro-cystic pathways, the initiating transcriptional events in cyst formation are unclear. By studying pre-cystic ADPKD mice, we found new candidate genes for cyst initiation.

Methods

Pkd2fl; CAG-CreERT2 pups received tamoxifen via IP injection on postnatal day 2 (P2). RNA was isolated on P6 and P10, followed by library preparation and analysis. Results were compared to published data and mouse and human kidney tissues were stained to confirm epithelial candidate localization.

Results

We found 91 differentially expressed genes (DEGs) in pre-cystic kidneys (P6) and 5,309 DEGs at the early cystic timepoint (P10) (FDR<0.05). P6 and P10 overlapping DEGs include 74 genes, defined as cyst initiation candidates (CICs). We characterized CICs using published datasets (bulk RNAseq from alternative early ADPKD models, single-cell RNAseq from healthy mouse kidney and human ADPKD patients). Tacstd2 emerged as a promising candidate due to its epithelial specificity. Experiments showed high Tacstd2 expression in cystic-lining epithelium in mouse and human tissue.

Conclusion

74 candidate cyst initiation genes warrant further investigation. Tacstd2 selectively labels cystic epithelium in Pkd2 mice and humans with ADPKD. Antibody drug conjugates targeting Tacstd2 in human epithelial tumors have been approved by the FDA for treatment of metastatic triple-negative breast cancer and urothelial cancer. Adapting this technology may prove efficacious in ADPKD.

Mouse kidney probed for Tacstd2, collecting duct marker AQP2, proximal tubule marker LTA. Nuclear marker DAPI.

Funding

  • Other NIH Support