Kidney Week

Abstract: FR-PO608

IP1 Deletion Rescues Kidney Cyst Formation in Pkd1 KO Mouse Models

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

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

Ario Mohammadi, MD

• Ghazanfari, Davoud, Brigham and Women's Hospital, Boston, Massachusetts, United States

Davoud Ghazanfari, PhD

• Ayub, Armaghan, Brigham and Women's Hospital, Boston, Massachusetts, United States

Armaghan Ayub, MBBS

• Zhou, Erica, Brigham and Women's Hospital, Boston, Massachusetts, United States

Erica Zhou

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

Jing Zhou, MD, PhD, FASN

Background

ADPKD (Autosomal Dominant Polycystic Kidney Disease) is a genetic disorder characterized by the development of multiple cysts in the kidneys. The disease is caused by mutations in PKD1 and PKD2, encoding PC1 and PC2 respectively. To date, PC1 and PC2 have been implicated in modulating a number of cellular events such as Ca²⁺ signaling, mTOR, cyclic AMP, Wnt, PCP, and STAT3 pathways. Currently, there is limited knowledge regarding the mechanism(s) by which the PKD1/2 mutations dysregulate these signaling pathways. Our research group and others have reported that simultaneous loss of genes including ift88, Wdr19, and CRTC2, in Pkd1 KO mice models rescues cystogenesis and disease progression demonstrating potential therapeutic targets to attenuate ADPKD. It has been reported that IP1 forms a complex with PC1 and regulates multiple biological functions critical in ADPKD. Thus, IP1 is a potential therapeutic target for ADPKD.

Methods

Mice homozygous with an inducible mutation in Pkd1 or Pkd1IP1 genes were generated by intraperitoneal injection of tamoxifen at 3 weeks postnatal. Mice were dissected after 10 weeks. Kidney/BodyWeight (K/BW) ratios were calculated to analyze phenotype changes in the Pkd1 KO and Pkd1IP1 DKO mice. Various techniques such as immunohistochemistry, immunostaining, and western blotting were utilized for analysis and validation.

Results

To see if IP1 deletion rescues Pkd1 KO-induced cystogenesis, the Pkd1 KO and Pkd1IP1 DKO mice were dissected and kidneys were harvested at 10 weeks PI. The (K/BW) were significantly increased in the Pkd1 KO mice and significantly reduced in the Pkd1IP1 DKO. Histology analysis confirmed cyst formation in the Pkd1 KO mice and that IP1 deletion reduced cystogenesis. Immunostaining analysis revealed that cilia were significantly shortened in the DKO mice compared to the Pkd1 KO mice. The western blotting analysis revealed that integrin α6 expression and Wnt and mTOR signaling pathways are dysregulated in the Pkd1 KO mice, which was significantly reduced in the DKO mice. Further analysis is being conducted to gain more insight into the mechanism by which IP1 deletion rescues ADPKD.

Conclusion

IP1 is a novel therapeutic target to rescue ADPKD. In vivo analysis revealed that IP1 deletion rescues Pkd1 KO-induced cytogenesis and shorten elongated cilia and corrected Wnt and mTOR signaling pathways in Pkd1 KO mouse model.

Funding

• NIDDK Support