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Kidney Week

Abstract: FR-PO548

Role of FBW7 in Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic

Authors

  • Patel, Maulin Mukeshchandra, The University of Oklahoma, Oklahoma City, Oklahoma, United States
  • Tsiokas, Leonidas, The University of Oklahoma, Oklahoma City, Oklahoma, United States
Background

ADPKD, caused by mutations mostly in PKD1 or PKD2 genes, is a leading cause of end-stage renal disease. Deleting structural components/proteins of cilia in mouse models of Pkd1 inactivation ameliorates ADPKD progression, highlighting the importance of cilia regulation in ADPKD. Our lab has shown that FBW7, a substrate recognition receptor of the SCFFBW7 Ubiquitin E3 ligase, can regulate ciliogenesis. It recognizes proteins with a specific phosphorylated sequence called "phospho-degrons" and targets them for degradation via the ubiquitin-proteasome system. In this study, we sought to investigate the role of FBW7 in ADPKD.

Methods

We adopted an early-onset ADPKD mouse model where we induced Pkd1 and/or Fbxw7 deletion in postnatal mice using a global tamoxifen-inducible Ubc-CreERT2.

Results

We found that UbcCreERT2; Pkd1f/f P16 pups develop cysts and significantly increased the Two kidney weight/body weight (2KW/BW) and cystic index, along with the loss of kidney function measured by levels of three different markers, BUN, Creatinine, and cystatin C in the blood serum compared to the WT pups. Furthermore, UbcCre; Pkd1f/f; Fbxw7f/+ & f/f p16 pups also developed cysts and increased 2KW/BW and cystic index similar to UbcCreERT2; Pkd1f/f P16 pups. However, surprisingly, UbcCre; Pkd1f/f; Fbxw7f/+ & f/f p16 pups showed significant rescue in the kidney function based on BUN, Cystatin C, and Creatinine levels in the serum compared to UbcCreERT2; Pkd1f/f P16 pups. Although the kidney function parameters in UbcCre; Pkd1f/f; Fbxw7f/+ & f/f p16 pups were still significantly higher compared to the WT pups, the fact that the UbcCre; Pkd1f/f; Fbxw7f/f p16 pups displayed improved kidney function despite having no significant changes in 2KW/BW, and cystic index compared to UbcCreERT2; Pkd1f/f P16 pups was exciting. This protective effect on kidney function upon loss of FBW7 was persistent when we analyzed P21 pups. Ubc-CreERT2; Fbxw7f/f pups do not show any apparent kidney phenotype.

Conclusion

Loss of FBW7 ameliorates ADPKD progression via proteomic reprogramming that perhaps partially uncouples the kidney function and cystogenesis, challenging the prevailing dogma that kidney function is secondary to defects/cysts in kidney architecture.

Funding

  • NIDDK Support