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Abstract: PO1550

Ferroptosis Promotes Cyst Growth in Autosomal Dominant Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Zhang, Xiaoqin, Mayo Clinic, Rochester, Minnesota, United States
  • Ding, Hao, Mayo Clinic, Rochester, Minnesota, United States
  • Li, Xiaoyan, Mayo Clinic, Rochester, Minnesota, United States
  • Harris, Peter C., Mayo Clinic, Rochester, Minnesota, United States
  • Li, Xiaogang, Mayo Clinic, Rochester, Minnesota, United States
Background

Ferroptosis is a newly discovered form of non-apoptotic cell death which is dependent on accumulation of lipid reactive oxygen species (ROS). Recent studies have shown that ferroptosis is involved in the pathophysiological processes of many diseases, such as cancer. However, the roles of ferroptosis in ADPKD remain unknown.

Methods

To evaluate whether ferroptosis occurs in ADPKD, we detected the levels of ROS with C11-BODIPY and 4-HNE staining, and the expression of glutathione peroxidase 4 (GPX4), a key protein in the ferroptotic pathway, by western blot and qRT-PCR in cystic cells and kidneys. To understand the role of ferroptosis in ADPKD, we treated Pkd1 mutant mice with erastin, a ferroptosis inducer, and Ferrostain-1, a ferroptosis inhibitor.

Results

We found that the levels of free radical-induced oxidation and 4-HNE, a biproduct of lipid peroxidation, were increased in Pkd1 mutant renal epithelial cells and tissues as examined by C11-BODIPY and 4HNE staining. Erastin treatment resulted in smaller-than-normal mitochondria with increased density, a morphological feature of ferroptotic cells, in Pkd1 mutant renal epithelial cells under electronic microscopy. We further found that treatment with erastin promotes cyst growth as seen by increased cystic index, kidney weight (KW)/body weight (BW) ratios, blood urea nitrogen (BUN) levels, cyst lining epithelial cell proliferation, and lipid peroxidation in Pkd1RC/RC mice (all p < 0.01). In contrast, treatment with Ferrostain-1 delayed cyst growth in early stage Pkd1flox/flox:Pkhd1-Cre mice and Pkd1RC/RC mice as seen by decreases in all the parameters observed in erastin treated mice. Treatment with erastin increased the activation of ERK, Stat3, Akt and Rb in Pkd1 mutant renal epithelial cells and tissues. Activation of Stat3 increased the expression of DNA methyltransferase 1 (DNMT1), leading to the binding of DNMT1 to the GPX4 promoter and decreased expression, resulting in the accumulation of ROS species to promote cystic renal epithelial cell ferroptosis. Treatment with Ferrostain-1 reversed all these processes in Pkd1 mutant renal epithelial cells and tissues.

Conclusion

Pkd1 mutation induced the downregulation of GPX4 via Stat3-DNMT1, resulted in accumulation of ROS species, and the induction of ferroptosis to promote renal cyst growth. Inhibition of ferroptosis may be a viable new therapy for ADPKD.

Funding

  • NIDDK Support