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Abstract: FR-PO293

The Ciliary Phosphoinositide Pathway Regulates the Level of Polycystins in Cilia

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic


  • Chen, Chuan, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Hu, Jinghua, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Ling, Kun, Mayo Clinic Minnesota, Rochester, Minnesota, United States

ADPKD is a progressive genetic disorder which is mainly caused by mutations in the PKD1 and PKD2. The dosage of functional polycystins strongly correlates with the disease severity. However, molecular mechanisms underlying the trafficking and maintenance of PC1/PC2 in cilia remain unclear.
Phosphoinositides (PIs) are a group of signaling phospholipids that regulate membrane trafficking. Abnormal phosphoinositide metabolism correlates with variant human diseases, including polycystic kidney. Recent studies showed that PI(4)P and PI(4,5)P2, exhibit unique compartmentalization in the ciliary membrane and regulate ciliary trafficking and signaling, suggest the PI pathway may function in the trafficking of polycystins.


We use small molecule inhibitors and location-directed protein expression to manipulate the PI contents in the context of cilia, and then determine the ciliary level of PC1 and PC2 using IF and immunoblotting.
We use the IMCD3 3D spheroid model and embryonic kidney culture to mimic cystogenesis.
We use the FlpIn system to generate several patient mutations of PC1 and PC2.


We found that approaches increasing the ciliary PI(4,5)P2 significantly increase the PC2 level in cilia in normal cells and cells carrying ADPKD mutations, such as GANAB and PKD1 p.R3277C. By generating more patient mutations using FlpIn system, we discovered the ciliary level of several mutated polycystins can be also restored by increasing the PI(4,5)P2 level.
More importantly, increasing PI(4,5)P2 in cilia reduces the cystic burden in the ADPKD disease model. Cyst index analysis indicated that our specific inhibitor significantly reduced the cyst formation both in vitro and ex vivo, and moderately reduced in vivo. In addition, this inhibitor showed no obvious effect on phosphated AKT or ERK expression, suggested that the impaired cystogenesis observed in the inhibitor groups very likely resulted from the recovered ciliary level of polycystins.


ADPKD is the most prevalent inherited progressive kidney disease with potential lethality. However, the effective treatment of ADPKD is extremely limited. We found that manipulating the ciliary PI pathway as well as their products significantly increases the ciliary dosage of polycystins, and exhibits suppression effects on renal cystogenesis. These results suggest that the ciliary PI pathway could be a novel therapeutic target for ADPKD.


  • NIDDK Support