Kidney Week

Abstract: FR-PO559

Repression of Foxo3-Gatm Accelerates Cystogenesis by Increasing Reactive Oxygen Species (ROS) in ADPKD

Session Information

• Genetic Diseases: Cystic - Basic
  November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Jun, Jaehee, Sookmyung Women's University, Yongsan-gu, Seoul, Korea (the Republic of)

Jaehee Jun,

• Park, Jong Hoon, Sookmyung Women's University, Yongsan-gu, Seoul, Korea (the Republic of)

Jong Hoon Park,

• Ko, Je Yeong, Sookmyung Women's University, Yongsan-gu, Seoul, Korea (the Republic of)

Je Yeong Ko,

• Ahn, Yejin, Sookmyung Women's University, Yongsan-gu, Seoul, Korea (the Republic of)

Yejin Ahn,

• Chaewon, Oh, Sookmyung Women's University, Yongsan-gu, Seoul, Korea (the Republic of)

Oh Chaewon,

• Min, Jinui, Sookmyung Women's University, Yongsan-gu, Seoul, Korea (the Republic of)

Jinui Min,

Group or Team Name

• Sookmyung Women's University.

Background

The most common inherited renal disorder and leading cause of genetic end-stage renal disease is ADPKD. The relationship between ADPKD and oxidative stress have reported in in the early stage with disease progression, however the mechanism of correlation remains unclear.

Methods

We generate Pkd1^flox:HoxB7-Cre and performed integrative analysis.
3D cell culture produced in vitro cyst formation, and we observed differences in cyst formation .

Results

We explored the mechanisms associated with FOXO3 in ADPKD through screening by integrative analysis since FOXO3 regulates mitochondrial gene expression. And notably, GATM were significantly reduced in ADPKD patients. Furthermore, GATM was decreased by FOXO3 knockdown. Additionally, Inhibition of FOXO3 decreased GATM in the mitochondria. Therefore GATM is regulated by FOXO3 in the mitochondria.
To verify the effect of Gatm on oxidative stress in ADPKD, we measured cellular ROS, DCFDA fluorescence intensity is elevated in Gatm knockdown. More specifically, Gatm silencing increased mitochondrial superoxide levels. This Gatm-mediated increase in superoxide levels was confirmed by co-staining with MitoSOX Red. To investigate the effect of Gatm on cyst formation in ADPKD, we experimented 3D cell culture and observed significantly promoted cyst progression with Gatm silencing.

Conclusion

We suggest a novel insight of cystogenesis, in which inhibited Foxo3 reduces Gatm expression, thereby increasing ROS and oxidative stress, consequently progressing cyst enlargement in ADPKD.