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Kidney Week

Abstract: SA-OR093

The Ciliary Phosphoinositide Pathway Controls the Dosage of Polycystins in Cilia

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic


  • Chen, Chuan, Mayo Clinic, Rochester, Minnesota, United States

ADPKD is a progressive genetic disorder characterized by the development of fluid-filled renal cysts. It is mainly caused by mutations in PKD1 and PKD2 genes encoding respectively PC1 and PC2. PC1 and PC2 function as a complex and localize predominantly in primary cilia. However, the molecular mechanism underlying the trafficking and maintenance of PC1/PC2 in cilia is unclear.
PIs are a group of signaling phospholipids that regulate membrane trafficking and organelle identity. Abnormal phosphoinositide metabolism correlates with variant human diseases. Recent studies showed that PI(4)P and PI(4,5)P2 exhibit unique compartmentalization in the ciliary membrane and regulate the ciliary trafficking and signaling, suggesting this PI pathway may function in the trafficking of polycystins to cilia.


We manipulate the PI contents and determine the ciliary level of PC1 and PC2 using IF. The global protein levels are determined by immunoblotting. We use the 3D spheroid model and the embryonic kidney culture to determine the effect of the ciliary PI pathway on renal cystogenesis. Moreover, in vitro cellular assays are used to monitor cell survival and proliferation.


We found increased PI(4,5)P2 level in ciliary membrane increases the ciliary level of PC2 in normal cells. Moreover, in renal epithelial cells carrying ADPKD mutations, the ciliary level of PC1 and PC2 can also be restored by increasing PI(4,5)P2 in cilia.
Then, we utilized 3D culture and embryonic kidney culture assays to detect the renal cystogenesis, and discovered that our specific inhibitor reduced the cyst formation both in vitro and ex vivo. In addition, the inhibitor showed no obvious effect on phosphated AKT or ERK expression, as well as cell proliferation in MTT assays, suggesting that the impaired cystogenesis were very likely resulted from recovered ciliary polycystins.


The effective treatment of ADPKD is extremely limited and Tolvaptan as the only FDA approved drug shows limited benefits with substantial side effects. The functional dosage of polycystins directly influences the disease severity in ADPKD patients. We found that manipulating the ciliary PI pathway as well as their products increases the ciliary polycystins, and exhibits suppression effects on cystogenesis. These results suggest that the ciliary PI pathway could be a novel therapeutic target for ADPKD.