Kidney Week

Abstract: FR-PO0659

Ciliary ARL13B Drives Renal Cystogenesis via Its GEF Activity for ARL3

Session Information

• Cystic Kidney Diseases: Basic and Translational Research
  November 07, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases

Authors

• Van Sciver, Robert E., Emory University School of Medicine, Atlanta, Georgia, United States

Robert E. Van Sciver, PhD

• Forster, Avery, Emory University School of Medicine, Atlanta, Georgia, United States

Avery Forster

• Caspary, Tamara, Emory University School of Medicine, Atlanta, Georgia, United States

Tamara Caspary, PhD

Background

Mutations in the polycystin genes, PKD1 and PKD2, are the most common cause of polycystic kidney disease (PKD). These genes encode for polycystin proteins (PC1 and PC2), which localize to the primary cilium, a specialized cellular organelle crucial for sensing extracellular signals. These proteins function in an inhibitory role within a cilia-dependent cyst activating (CDCA) pathway, yet, the precise molecular driver(s) responsible for cystogenesis remain largely unknown. ARL13B, an ADP-ribosylation factor (ARF)-like GTPase, is enriched in primary cilia and possesses both GTPase activity and guanine nucleotide exchange factor (GEF) activity for ARL3, another ciliary GTPase. The study used two distinct mouse alleles of Arl13b to dissect the contributions of ARL13B's ciliary localization and GEF activity to PKD pathogenesis.

Methods

The study employed genetically engineered mouse models carrying specific Arl13b mutations – Arl13b^V358A, encoding an enzymatically normal ARL13B protein that is undetectable in cilia, and Arl13b^R79Q, encoding a GEF-deficient ARL13B protein that still localizes to cilia. These mouse models, in combination with Pkd1-deficient mice, allowed detailed examination of ARL13B's role in the CDCA pathway. We examined several hallmarks of PKD including kidney size, morphology, renal physiology, fibrosis, injury, and WNT signaling using mouse genetics, histology, and cell and molecular biology techniques.

Results

Our study revealed that ciliary ARL13B functions within the CDCA pathway to drive renal cystogenesis in Pkd1-deficient mice. We specifically show that ARL13B’s GEF activity for ARL3 is critical in driving cystogenesis in Pkd1-deficinet mouse models. Double mutant mice lacking both Pkd1 and ciliary ARL13B or Pkd1 and ARL13B GEF activity significantly suppressed cystic phenotypes including kidney morphology, injury, fibrosis, and WNT/β-catenin/cyclin D1 signaling compared to loss of Pkd1 single mutant animals.

Conclusion

This study provides compelling evidence that ciliary ARL13B plays a critical role in the CDCA pathway and that its GEF activity for ARL3 is a major driver of renal cystogenesis in a mouse model of PKD. These findings identify a key molecular mechanism underlying PKD pathogenesis and suggest that targeting ARL13B's GEF activity may represent a potential therapeutic strategy for this disease.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025nme16egq