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Abstract: TH-PO747

RIPK3 Promotes Mitochondrial Fission and Dysfunction via PGAM5-Drp1 Signaling During Diabetic Podocyte Injury

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Kang, Jeong suk, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea (the Republic of)
  • Cho, Nam-Jun, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea (the Republic of)
  • Lee, Seong Woo, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea (the Republic of)
  • Lee, Ji-Hye, Department of Pathology, Soonchunhyang University Cheonan Hospital, Cheonan, Korea (the Republic of)
  • Park, Samel, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea (the Republic of)
  • Gil, Hyo-Wook, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea (the Republic of)
  • Son, Seung Seob, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea (the Republic of)
  • Lee, Donghyeong, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea (the Republic of)
  • Jeong, Hee Seul, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea (the Republic of)
  • Lee, Eun Young, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea (the Republic of)
Background

Receptor-interacting protein kinase (RIPK)3 is an essential molecule for necroptosis and its role in kidney fibrosis has been investigated using various kidney injury models. However, the relevance and the underlying mechanisms of RIPK3 of podocyte injury in DKD are poorly understood. In this study, we investigated the role of RIPK3 in kidney injury of DKD and elucidated the underlying mechanism.

Methods

We evaluated the association of RIPK3 on clinical indices of DKD in the kidneys from diabetic patients and animals. To investigate the role of RIPK3 in glomerular damage of DKD, diabetes was induced by a high-fat diet in Ripk3 knockout (KO) mice and cultured podocytes were stimulated with high glucose with or without RIPK3 inhibitor GSK872.

Results

RIPK3 level was upregulated in podocytes and plasma from human DKD cohort. Such upregulation was correlated with podocyte loss, albuminuria, and poor renal outcome. RIPK3 deficiency in DKD mice improved albuminuria, podocyte numbers, and renal histopathological features including foot process effacement and glomerular basement membrane (GBM) thickening. Increased mitochondrial fragmentation, upregulated mitochondrial fission-related proteins such as phosphoglycerate mutase family member 5 (PGAM5) and dynamin-related protein 1 (Drp1), and mitochondria dysfunction were decreased in RIPK3-depleted diabetic podocytes both in vitro and in vivo. By contrast, RIPK3 overexpression was sufficient to decrease oxygen consumption rate and increase PGAM5 expression and mitochondrial fragmentation due to mitochondrial translocation of Drp1.

Conclusion

RIPK3 is associated with diabetic podocytopathy, likely by regulating mitochondrial fission via PGAM5-Drp1 signaling. Targeting RIPK3 might be a promising therapeutic option for treating DKD.

Funding

  • Government Support – Non-U.S.