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Abstract: TH-PO413

Hypoxia-Inducible Factor-Prolyl Hydroxylase (HIF-PHD) Inhibitor Accelerates Liver Cyst Growth in Autosomal Dominant Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic

Authors

  • Takenaka, Shun, Hokkaido Daigaku Daigakuin Igaku Kenkyuin, Sapporo, Hokkaido, Japan
  • Nishio, Saori, Hokkaido Daigaku Daigakuin Igaku Kenkyuin, Sapporo, Hokkaido, Japan
Background

It has been reported that hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitor promotes renal cyst formation due to activation of HIF. However, the effect on liver cysts is unclear. In this study, we will analyze the effects of HIF-PHD inhibitor on liver cysts and their mechanisms.

Methods

We used Pkd1 conditional knockout mice (Pkd1flox/flox Mx-1-Cre mice). Mice were injected with polyinosinic-polycytidylic acid for 6 consecutive days at 5 days of age to inactivate Pkd1. Both cystic and non-cystic mice were randomly assigned to vehicle-only and enarodustat-treated groups (non-Cystic (CT), non-Cystic (Ena), Cystic (CT) and Cystic (Ena) group). Enarodustat was mixed in feed. Mice were sacrificed at 8 weeks of age. We analyzed the phenotype of cystic livers by liver/body weight ratio (LV/BW), and cystic index (CI) which was defined as the percentage of areas occupied by cysts. For evaluation of cell proliferation, immunohistochemical staining for proliferating cell nuclear antigen (PCNA) was performed. We also performed western blotting of signaling pathway of cyst growth by using whole liver.

Results

There was no significant difference in body weight among 4 groups. Mice treated with enarodustat exhibited a significant high level of hematocrit in both non-Cystic (CT) and Cystic (Ena) groups (p<0.01). There was no significant difference in LW/BW, but the Cystic Index (CI) of liver was significantly elevated in Cystic (Ena) group (30.8±8.5%) than in Cystic (CT) group (18.0±5.9%; p<0.05). Masson-Trichrome staining showed accelerated liver fibrosis in the Cystic (Ena) group. PCNA positive cells in the cystic epithelial cells was higher in the Cystic (Ena) group than in the Cystic (CT) group (p=0.02). In immunohistochemical staining of glucose transporter 1, the positive area rate was significantly higher in the Cystic group than in the non-Cystic group and was significantly expressed in the Cystic (Ena) group. Western blotting showed that phosphorylated Erk and phosphorylated p70S6K tended to be upregulated in the Cystic (Ena) group.

Conclusion

HIF-PHD inhibitor accelerated liver cyst formation via proliferation of cyst lining cells by activating the MAPK pathway and mTOR pathway.