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Abstract: FR-PO258

Autophagy Is Dynamically Dysregulated Along the Pathogenesis of Autosomal Dominant Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic


  • Lavin, Andrew Michael, Mayo Clinic Research Rochester, Rochester, Minnesota, United States
  • Zhu, Ping, Mayo Clinic Research Rochester, Rochester, Minnesota, United States
  • Harris, Peter C., Mayo Clinic Research Rochester, Rochester, Minnesota, United States
  • Xu, Xiaolei, Mayo Clinic Research Rochester, Rochester, Minnesota, United States
  • Lin, Xueying, Mayo Clinic Research Rochester, Rochester, Minnesota, United States

Abnormal autophagy has been noted in various models of PKD. However, a consensus is lacking and treatment targeting autophagy gives rise to contradictory results, underscoring the complexity of functions of autophagy in PKD. Here, we conducted a detailed analysis of autophagy dysregulation in a mouse model of ADPKD.


Pkd1RC/RC mouse that contains a disease variant, PKD1 p.R3277C, was crossed into a transgenic Tg(EGFP-Lc3) reporter mouse. Autophagy was assessed at different time points during the disease progression via western blotting, immunofluorescence staining, and qPCR. To measure autophagic flux, BafA1, an inhibitor of autophagosome-lysosome fusion, was used.


At 1 month of age when total kidney weight/body weight ratio (2KW/BW) in RC/RC mice was only doubled compared with wild-type animals, LC3-II proteins were accumulated at a steady state and failed to further accumulate in the presence of BafA1, indicating insufficient autophagic flux. GFP-LC3 puncta were mainly detected in the non-cystic PT tubules, suggesting autophagy dysregulation was more likely a primary defect to Pkd1 mutation than secondary to cyst formation. Essential autophagy proteins such as Becn1, Atg7, and Lamp2 were normally expressed while Tfeb, a transcription factor implicated in the autophagic flux regulation and oncogenic proliferation, was specifically downregulated in the PT tubules. At 6 months when 2KW/BW in the RC/RC mice was 5-6 times higher than wild-type controls, steady state LC3-II levels were elevated and autophagic flux was recovered. Becn1, Atg7, Lamp2, and Tfeb were all overexpressed, and Tfeb nuclear localization was significantly increased in both the PT and CD tubules.


We found dynamic autophagy dysregulation in the Pkd1RC/RC mouse model of ADPKD, i.e., impaired cargo clearance in the early phase, and adaptive/maladaptive autophagy activation in the later phase, and a spatial- and temporal-dependent dysregulation of Tfeb. Our study suggests a time-dependent mechanism that needs to be considered when developing an autophagy-based therapy for ADPKD.