Kidney Week

Abstract: SA-PO0130

Polycystin-2-Like 1 (PC2L1) Does Not Worsen Early Polycystin-2 Deficiency-Driven Renal or Hepatic Cystogenesis in Mice

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

• Zahir, Danish, Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, United States

Danish Zahir

• Mohammadi, Ario, Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, United States

Ario Mohammadi, MD

• Qadeer, Abdul, Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, United States

Abdul Qadeer, MBBS

• Ayub, Armaghan, UPMC Mercy, Pittsburgh, Pennsylvania, United States

Armaghan Ayub, MD

• Li, Shuang, Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, United States

Shuang Li, MD, PhD

• Baloch, Maryam F., Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, United States

Maryam F. Baloch, MBBS

• Zhou, Jing, Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, United States

Jing Zhou, MD, PhD, FASN

Group or Team Name

• Zhou Lab

Background

ADPKD is caused by mutations in PKD1 or PKD2, which encode polycystin-2 (PC2), a transient receptor potential (TRP) family cation channel essential for ciliary calcium (Ca²⁺) signaling in renal epithelial cells. PC2L1, encoded by PKD2L1, is a Ca²⁺-permeable non-selective cation channel and shares high structural homology with PC2. PC2L1 localizes to primary cilia in renal epithelial cells and hippocampal neurons, and recent pore-swapping knock-in studies in mice have suggested that altered PC2L1 channel properties can induce mild cystogenesis when substituted into the Pkd2 locus.

Methods

We generated global Pkd2l1 single knockout (SKO) and tamoxifen-inducible Pkd2 SKO and double knockout (DKO) mice. Kidney-to-body weight (K/BW) and liver-to-body weight (LW/BW) ratios were assessed at 10 weeks post-induction (PI) in both sexes, with an additional 14-week PI male cohort with ongoing data collection. Parametric t-tests and one-way ANOVA were used for statistical analysis. In parallel, a single-nucleus RNA-seq transcriptomic database on a Pkd1 SKO mouse model was analyzed across three disease stages (P66, P100, P130).

Results

Pkd2l1 KO mice exhibit normal kidneys and liver at all stages. At 10 weeks PI, DKO mice exhibit significantly increased K/BW ratios compared with WT, but not significantly different from the Pkd2 SKO mice. The male DKO mice demonstrated a modest but significant difference in LW/BW compared with Pkd2 SKO mice, unlike the female DKO mice. These findings may suggest a potential sex-dependent hepatic effect.
Preliminary 14-week PI male data showed increased renal and hepatic disease burden in DKO mice, although the interpretation is underpowered by the limited sample size and variability. Transcriptomic analysis revealed segment-specific Pkd2l1 remodeling in late-stage disease (P130), with increased expression in collecting duct principal cells and reduced expression in ascending thin limb segments relative to the control mice in a fraction of the nuclei.

Conclusion

PC2L1 does not worsen early PC2-dependent renal or hepatic cystogenesis and progression in vivo. However, sex-dependent hepatic differences together with nephron segment-specific transcriptional remodeling of Pkd2l1 in single-nucleus transcriptomic datasets hint at a context-dependent role for PC2L1 in polycystin biology that may vary across tissue compartments and disease stages.

Funding

• Government Support – Non-U.S.