Kidney Week

Abstract: SA-PO0117

Glis2 Inactivation Attenuates Renal Cystogenesis in Orthologous Missense Mouse Models of ADPKD

Session Information

• ADPKD and Cystic Kidney Disease - 3
  October 24, 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

• Bhardwaj, Rishi, Yale School of Medicine, New Haven, Connecticut, United States

Rishi Bhardwaj, PhD

• Hasan, Fatema, Yale School of Medicine, New Haven, Connecticut, United States

Fatema Hasan, PhD

• Rehman, Michael, Yale School of Medicine, New Haven, Connecticut, United States

Michael Rehman, PhD

• Dong, Ke, Yale School of Medicine, New Haven, Connecticut, United States

Ke Dong, MD

• Tian, Xin, Yale School of Medicine, New Haven, Connecticut, United States

Xin Tian, MD

• Krappitz, Matteus, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Matteus Krappitz, DrMed

• Somlo, Stefan, Yale School of Medicine, New Haven, Connecticut, United States

Stefan Somlo, MD

• Fedeles, Sorin V., Yale School of Medicine, New Haven, Connecticut, United States

Sorin V. Fedeles, PhD, MBA

Background

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of end-stage kidney disease and is driven primarily by mutations in PKD1 (~77%) and PKD2 (~15%) that produce progressive cyst formation. A recent study reported that inactivation of the transcriptional regulator Glis2 slows cystic progression in Pkd1-null mice. To further establish translational relevance, we asked whether Glis2 inactivation attenuates disease in orthologous, pathogenic mutation-based missense mouse models of ADPKD.

Methods

We generated two knock-in alleles modeling human ADPKD mutations: a PC1 hypomorphic missense allele (mouse R2216W corresponding to human R2220W; previously published) and a complete GPS cleavage–defective allele (mE2766K/hE2771K). Each line was crossed onto a conditional Pkd1flox/flox; Pax8-rtTA; TetO-Cre background carrying a Glis2flox/flox allele to generate Pkd1R2216W/flox; Glis2flox/flox; Pax8-rtTA; TetO-Cre or Pkd1E2216K/flox; Glis2flox/flox; Pax8-rtTA; TetO-Cre double mutant mice. Floxed-allele inactivation was done via doxycycline i.p. injection at P10 and P11 with the phenotype assessed at P24. Phenotypic read-outs included kidney-to-body weight (KW/BW) ratio, cystic index and renal function.

Results

In the Pkd1R2216W/flox; Glis2flox/flox; Pax8-rtTA; TetO-Cre mice at P24, Glis2 inactivation produced a significant reduction in KW/BW ratio (2.18±1.19 vs 9.00±3.18,**p=0.007) and cystic index (14.25±6.22 vs 54.91±8.71, **p=0.001) versus Pkd1R2216W/flox; Pax8-rtTA; TetO-Cre cystic littermate mice. The Pkd1E2216K/flox; Pax8-rtTA; TetO-Cre cleavage-defective mice exhibited a very severe baseline cystic phenotype (more severe than the Pkd1-R2216W counterpart), yet in the presence of Glis2 inactivation they displayed a very significant decrease in KW/BW ratio (5.92±4.15 vs 20.36±1.91), and reduced cystic index (39.92±13.76 vs 69.68±1.67). Finally, in alignment with previously published findings, Pkd1flox/flox; Glis2flox/flox; Pax8-rtTA; TetO-Cre mice displayed a much milder disease presentation vs. Pkd1flox/flox;Pax8-rtTA; TetO-Cre SKO animals (KW/BW ratio-6.03±3.66 vs 17.05±3.75; Cystic Index-38.83±10.47 vs 69.73±2.58).

Conclusion

These data provide the first evidence that Glis2 inactivation mitigates renal cystogenesis in orthologous missense models of ADPKD, supporting the role of Glis2 as a translationally relevant modifier and candidate therapeutic target.

Funding

• Other U.S. Government Support