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Abstract: PO2509

Peroxiredoxin 5 Regulates Cyst Growth and Ciliogenesis via Modulating Aurora A and Plk1 Stability and Wnt Signaling Activation

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Agborbesong, Ewud, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
  • Zhou, Xia, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
  • Li, Xiaogang, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
Background

Peroxiredoxin 5 (Prdx5) is an antioxidant enzyme that catalyzes the reduction of H2O2 and alkyl hydroperoxide and plays a protective role in neurological and cardiovascular disorders. However, the role and mechanism of Prdx5 in autosomal dominant polycystic kidney disease (ADPKD) is unknown.

Methods

To investigate the role and mechanism of Prdx5 on cyst growth and cilia biogenesis in ADPKD, we knocked down Prdx5 in mIMCD3 and RPE cells with siRNA and shRNA, and performed Western blot, qRT-PCR and immunostaining analysis in renal epithelial cells and tissues. A 3-dimensional cell culture system was used to evaluate the effect of Prdx5 knockdown on cyst growth.

Results

We found that Prdx5 was downregulated in cystic renal epithelial cells and tissues. Knockdown of Prdx5 resulted in: 1) abnormal centrosome amplification and multipolar spindle formation in mIMCD3 cells; 2) the upregulation of Polo-like kinase 1 (Plk1) and Aurora kinase A (AurA), essential in cell division and checkpoint regulation of mitosis; 3) the formation of cysts in a three-dimensional matrigel culture system using IMCD3 cells, which correlated with the phosphorylation and activation of PKD associated proliferation signaling, including ERK and mTOR; and 4) impaired primary cilia formation in mIMCD3 and RPE cells, which could be rescued by inhibition of Plk1 activity. In addition, we show that Prdx5 plays a crucial role in the regulation of Wnt signaling pathway activity in renal epithelial cells. Stimulation of Wnt3a ligand had no effect on ciliogenesis in Prdx5 knockdown cells. In contrast, stimulation of Wnt5a exacerbated ciliogenesis defect in Prdx5 knockdown cells. Consistent with Wnt5a activity on regulating primary cilia biogenesis, knockdown of Prdx5 decreased the recruitment of centriolar satellites PCM1 and CEP290, to the centrosome/basal body.

Conclusion

This is the first study to show that Prdx5 regulates cyst formation and cilia biogenesis via affecting the stability of Plk1 and AurA, and the activation of PKD associated signaling pathways. Prdx5 could also control noncanonical Wnt5a-dependent regulation of ciliogenesis, a cascade of events that regulate the recruitment of centriolar satellites necessary for, primary cilia biogenesis.

Funding

  • Other NIH Support