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Abstract: FR-PO285

Polycystins Are Required for Renal Tubulointerstitial Fibrosis

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic

Authors

  • Wang, Yanzhe, Shuguang Hospital, ShangHai, China
  • Wu, Ming, Shuguang Hospital, ShangHai, China
  • Ye, Chaoyang, Shuguang Hospital, ShangHai, China
Background

Renal fibrosis is the common pathway of various chronic kidney diseases progressing to end stage renal failure. Polycystin-1 (encoded by PKD1 gene) and polycystin-2 (encoded by PKD2 gene) form a transmembrane complex and function as a stress sensor, which is located in the primary cilia. Polycystins are involved in the disease condition of different organs. Mutation of PKD genes causes autosomal dominant polycystic kidney disease and deletion of polycystin attenuates heart injury induced cardiac fibrosis. The role of polycystins in renal tubulointerstitial fibrosis is currently unclear.

Methods

Unilateral ureteral obstruction (UUO), unilateral ischemia-reperfusion injury (UIRI), aristolochic acid or folic acid induced mouse models of renal fibrosis were established for this study.

Results

Here we showed that polycystin-2 is up-regulated in these three mouse models of renal fibrosis and tightly correlated with the expression of collagen-I in a time dependent manner. Treatment with triptolide inhibited the expression of polycystin-2 and pro-fibrotic markers in UUO and UIRI models. Moreover, triptolide or PKD2 siRNA inhibited the expression of polycystin-2 and pro-fibrotic markers in vitro. Using Pkd2 conditional knockout mice, we showed that genetic deletion of Pkd2 reduced the expression of pro-fibrotic markers in UUO kidneys. Polycystin-1 was also up-regulated in renal fibrotic models and conditional deletion of Pkd1 reduced the expression of pro-fibrotic markers in UUO or folic acid induced fibrotic kidneys. Furthermore, the expression of the methyltransferase EZH2 is positively correlated with the expression of polycystins in fibrotic kidneys. Conditional knockout of EZH2 attenuated the anti-fibrotic responses induced by Pkd1 deletion in UUO kidneys.

Conclusion

In conclusion, polycystins are up-regulated in fibrotic kidneys and promote renal tubulointerstitial fibrosis through up-regulation of EZH2, suggesting that primary cilia are required for renal tubulointerstitial fibrosis.