Kidney Week

Abstract: FR-PO606

Role of Valosin-Containing Protein (VCP) in Ciliary Morphology and ADPKD: Exploring VCP as a Novel Genetic Interactor in Disease Progression

Session Information

• Cystic Kidney Diseases: Mechanisms and Models
  October 25, 2024 | 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: Cystic

Authors

• Pioppini, Carlotta, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany

Carlotta Pioppini, MS, MSc

• Bhardwaj, Rishi, Yale University, New Haven, Connecticut, United States

Rishi Bhardwaj, PhD

• Fedeles, Sorin V., Yale University, New Haven, Connecticut, United States

Sorin V. Fedeles, PhD, MBA

• Yilmaz, Duygu Elif, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany

Duygu Elif Yilmaz, MSc, PhD

• Krappitz, Matteus, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany

Matteus Krappitz, DrMed

Background

Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disorder characterized by the progressive development of fluid-filled cysts in the kidneys, leading to organ enlargement and functional impairment. The main causative genes encode for the ciliary proteins PC1 and PC2, which position ADPKD amidst the spectrum of ciliopathies. Within PKD1-deficient cells, the accumulation of misfolded PC1 and PC2 proteins triggers the unfolded protein response (UPR). In this study, we investigated the genetic relationship between an associated interactor of the UPR, Valosin-containing protein (VCP), and PC1 dependent cystogenesis. Finally, we elucidate VCP's dual engagement as a ciliary protein, as well as its regulatory role in cilia morphology.

Methods

IMCD3^wt and IMCD3^Pkd1-/- were treated with both pharmacological inhibitor of VCP or anti-VCP siRNA for 24 hours. Gene and protein expressions were detected respectively via qRT-PCR and western blotting. CelltiterGlo viability assay was used for cell viability analysis. Primary cilia were isolated from Pkd1^V5/+cells and cilia localization of VCP was detected via confocal microscopy.

Results

VCP was identified as a ciliary protein in renal epithelial cells. By inhibiting VCP using pharmacological agents and siRNA-mediated genetic suppression, ciliary length was decreased for both treatments. Importantly, inhibition of VCP selectively decreased the viability of Pkd1 deficient cells by upregulating ER-dependent apoptotic pathways. This selective response highlights a novel therapeutic approach for targeting cells responsible for cyst development in ADPKD. The findings suggest that VCP is involved in ciliary dynamics but also in cellular survival mechanisms underpinning cystogenesis.

Conclusion

This study confirms the critical involvement of VCP in regulating ciliary morphology and suggesting its potential as a therapeutic target in ADPKD. By proving that VCP inhibition selectively reduced the viability of Pkd1 deficient cells while increasing ER-dependent apoptosis, our research implicates VCP as a novel viability factor of cyst lining cells . These novel insights open new perspectives for the development of targeted therapies aimed at modulating ciliary morphology and inducing apoptosis in cyst-forming cells.

Funding

• Government Support – Non-U.S.