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Kidney Week

Abstract: TH-PO689

PS-341 Attenuates the Progression of Autosomal Dominate Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic

Author

  • Chen, Meihan, Changzheng Hospital Second Military Medical University, Rochester, Minnesota, United States
Background

The proteasome, which is a key component of the ubiquitin-proteasome pathway, has emerged as an important cancer therapeutic target. PS-341 (also called Bortezomib or Velcade) is the first proteasome inhibitor approved for multiple myeloma and has been tested in many clinical trials against other types of cancers. One of the mechanisms by which PS-341 exerts its anticancer effect is inactivation of nuclear factor-kB (NF-kB) through prevention of IkBa degradation.

Methods

Pkd1 conditional knock out mice were injected intraperitonealy with ps-341 0.3mg/kg twice a week from postnatal 15th day.Then cacrificed at postnatal 32th day. Serum was collected to test the BUN and creatinine levels.We use IHC to measure protein levels of NF-kB pathways and PCNA,TUNEL and Flow cytometry to detect apoptosis,MTT to test proliferation.

Results

In this study, we showed that PS-341 can effectively inhibited cyst growth in Pkd1 conditional knock out mice. PS-341 attenuates the progression of PKD through alleviating the BUN and serum creatinine levels in Pkd1 conditional knock out mice as well as improving the survival rate. However we didn’t found a decreased level of NF-kB which reveals that PS-341 may not retard disease progression through NF-kB pathway. However we found that PS-341 inhibits renal epithelial cells proliferation and promotes renal epithelial cells apoptosis in vivo and in vitro.

Conclusion

Collectively, these findings suggest that PS-341 inhibits renal epithelial cells proliferation and promotes apoptosis which provides a new strategy for treating and preventing the progression of ADPKD in the future.

Funding

  • Government Support - Non-U.S.