Kidney Week

Abstract: FR-PO0080

Adult Knock-In Zebrafish Model of ADPKD Enables Identification of Genetic Modifiers of Cystic Disease

Session Information

• ADPKD and Cystic Kidney Disease - 2
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

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

Authors

• Yang, Cuicui, Mayo Clinic Department of Biochemistry and Molecular Biology, Rochester, Minnesota, United States

Cuicui Yang, MBBS, PhD

• Zhu, Ping, Mayo Clinic Department of Biochemistry and Molecular Biology, Rochester, Minnesota, United States

Ping Zhu, PhD

• Yoon, Baul, Mayo Clinic Department of Biochemistry and Molecular Biology, Rochester, Minnesota, United States

Baul Yoon, PhD

• Harris, Peter C., Mayo Clinic Department of Biochemistry and Molecular Biology, Rochester, Minnesota, United States

Peter C. Harris, PhD

• Xu, Xiaolei, Mayo Clinic Department of Biochemistry and Molecular Biology, Rochester, Minnesota, United States

Xiaolei Xu, PhD

• Lin, Xueying, Mayo Clinic Department of Biochemistry and Molecular Biology, Rochester, Minnesota, United States

Xueying Lin, PhD

Background

Autosomal-dominant polycystic kidney disease (ADPKD) is one of the most prevalent and potentially life-threatening genetic disorders. Patients with ADPKD exhibit highly variable disease severity, in which genetic modifiers are thought to play an important role. However, the identities of these genetic modifiers remain largely unknown due to the lack of efficient discovery methods.

Methods

To address this challenge, we generated a pkd1^RC/RC knock-in zebrafish carrying the well-characterized pathogenic PKD1 variant p.R3277C and systematically analyzed renal phenotypes during disease progression. Histology, immunostaining, and RT-qPCR were performed to evaluate cyst formation, immune infiltration, fibrosis, and cellular senescence-associated phenotypes. To facilitate rapid modifier discovery, we applied a microhomology-mediated end joining (MMEJ)-based F0 genetic screening strategy in this model.

Results

Adult pkd1^RC/RC zebrafish recapitulated key pathological features observed in rodent models and human patients, including progressive kidney cyst formation, immune cell infiltration, inflammation, fibrosis, and cellular senescence-associated phenotypes. Using the F0 screening platform to target genes associated with senescence and premature aging, we identified several candidate modifiers, including gpnmb. Disruption of gpnmb exerted protective effects, as evidenced by reduced cyst burden, decreased macrophage accumulation, and normalization of profibrotic gene expression in pkd1^RC/RC zebrafish. Notably, gpnmb expression was highly enriched in renal macrophages in zebrafish and mouse models, as well as in human patients, suggesting a conserved macrophage-involved role across species.

Conclusion

Together, these findings established an adult zebrafish model of ADPKD and a scalable F0-based screening platform for systematic identification of genetic modifiers, providing an experimentally tractable approach for uncovering mechanisms underlying disease variability.

Acknowledgment

We thank the members of the Xu laboratory for technical support and discussion.

Funding

• NIDDK Support