Abstract: SA-PO469
Genetic Reduction of Cilium Length by Targeting Ift88 Impedes Kidney and Liver Cyst Formation in Autosomal Polycystic Kidney Disease Mouse Models
Session Information
- Cystic Kidney Diseases: Basic/Translational
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1001 Genetic Diseases of the Kidneys: Cystic
Authors
- El-Jouni, Wassim, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Behera, Tapas Ranjan, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Ajay, Amrendra Kumar, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Zhou, Jing, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
Group or Team Name
- Zhou Lab
Background
Mutations in polycystin-1 (PC1) and -2 (PC2), products of the PKD1 and PKD2 genes, cause autosomal dominant polycystic kidney disease (ADPKD). They localize to the primary cilia; however, their ciliary function is in dispute. The loss of either the cilia or PC1 or PC2 causes cyst in orthologous mouse models. Cystogenesis is inhibited in the absence of both cilia and PC1 or PC2. How the cilia and PC1 or PC2 interact to regulate cystogenesis is still unknown. The role of intraflagellar transport proteins in Pkd1-deficient mice is also unknown.
Methods
In this study we used human and mouse kidney tissues to study the correlation between cilia length and cyst formation. We developed Pkd1 and Pkd2 single and double knockouts with Ift88 to thoroughly investigate the correlation between cilia length and cystogenesis in mice and to identify downstream signaling targets.
Results
1) We report, for the first-time that cilium length is elongated in human ADPKD kidneys. 2) We found similar elongation in Pkd1 and Pkd2 knockout mice following polycystin inactivation. 3) We show that inactivating the intraflagellar transport protein Ift88 in Pkd1-deficient mice and Pkd2-deficient mice shortens the elongated cilia, impedes kidney and liver cystogenesis and reduces cell proliferation. 4) Multi-stage in vivo analysis of signaling pathways revealed a novel early, and sustained activator in disease onset and progression in Pkd2 single knockout (SKO) which is rescued in Pkd2 and Ift88 double knockout (DKO) mouse kidneys. 5) On the other hand, ERK pathway was activated in the SKO but no rescue was observed in the DKO mouse kidneys.
Conclusion
Our findings advocate an essential role of polycystins in the structure and function of the primary cilia and implicate a novel target as a key inducer of cystogenesis downstream of the primary cilia. These data suggest that modulating cilium length and/or its associated signaling events may offer novel therapeutic approaches for ADPKD.
Funding
- NIDDK Support