Kidney Week

Abstract: SA-PO274

5-Lipoxygenase Inhibition Ameliorates Diabetic Kidney Disease by Attenuating Renal Tubular Epithelial Cell Ferroptosis

Session Information

• Diabetic Kidney Disease: Basic - 2
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 701 Diabetic Kidney Disease: Basic

Authors

• Ha, Min Heui, CHA University Bundang Medical Center, Seongnam, Gyeonggi-do, Korea (the Republic of)

Min Heui Ha, MS

• An, Hyun-Ju, CHA University Bundang Medical Center, Seongnam, Gyeonggi-do, Korea (the Republic of)

Hyun-Ju An

• Sung, Min ji, CHA University Bundang Medical Center, Seongnam, Gyeonggi-do, Korea (the Republic of)

Min ji Sung, MS

• Jeong, Hyeyun, CHA University Bundang Medical Center, Seongnam, Gyeonggi-do, Korea (the Republic of)

Hyeyun Jeong, MD

• Baek, Jihyun, CHA University Bundang Medical Center, Seongnam, Gyeonggi-do, Korea (the Republic of)

Jihyun Baek, MD, DrMed

• Lee, So-young, CHA University Bundang Medical Center, Seongnam, Gyeonggi-do, Korea (the Republic of)

So-young Lee, MD, DrMed, PhD

• Lee, Yu ho, CHA University Bundang Medical Center, Seongnam, Gyeonggi-do, Korea (the Republic of)

Yu ho Lee, MD, PhD

Background

The enzyme 5-lipoxygenase plays a pivotal role in the conversion of arachidonic acid into 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which is a key source of lipid peroxides and leukotrienes. This study aims to elucidate the pathophysiological implications of 5-lipoxygenase in diabetic kidney disease (DKD), focusing on its impacts on lipid peroxidation and tubular cell ferroptosis.

Methods

HKC-8 cells, a human-derived renal proximal tubular cell line, was used to perform in vitro experiments. Diabetes induction in male C57BL/6J mice was achieved through streptozotocin injection. Zileuton was used to inhibit 5-lipoxygenase activity.

Results

Hyperglycemic stimuli upregulated the expression of 5-lipoxygenase both in HKC-8 cells. The overexpression of 5-lipoxygenase aggravated hyperglycemia-induced increases in the expression of profibrotic cytokines and reactive oxygen species (ROS) production, while its suppression mitigated these detrimental effects. High glucose also led to downregulations of glutathione peroxidase 4 (GPX4) and upregulations of Acyl-CoA synthetase long chain family member 4 (ACSL4), ferritin heavy chain 1 (FTH-1), and malondialdehyde (MDA), indicating the activation of pro-ferroptotic pathways. The overexpression of 5-lipoxygenase exaggerated hyperglycemia-induced ferroptotic cell death, which is attenuated by the inhibition of 5-lipoxygenase or ferrostatin-1 treatment . Additionally, streptozotocin-induced diabetic mice exhibited worse kidney function and interstitial fibrosis in association with decreased GPX4 and increased ACSL4 and FTH-1 levels compared to normoglycemic mice. Zileuton administration significantly ameliorated these hyperglycemia-induced kidney dysfunction and ferroptosis activation.

Conclusion

These findings demonstrate the central role of 5-lipoxygenase in intracellular lipid peroxidation and subsequent tubular cell ferroptosis under sustained hyperglycemic conditions. Inhibition of 5-lipoxygenase not only mitigates ferroptotic tubular cell death but also alleviates hyperglycemia-induced renal dysfunction. This suggests that 5-lipoxygenase could serve as a potential therapeutic target for the treatment of DKD.