Abstract: PO0945
Beneficial Effect of Chloroquine and Amodiaquine on Diabetic Tubulopathy by Attenuating Mitochondrial Nox4 and Endoplasmic Reticulum Stress
Session Information
- Diabetic Kidney Disease: New Pathways and Therapies
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Lee, So-young, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea (the Republic of)
- Yang, Dong Ho, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea (the Republic of)
- Jeong, Hye yun, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea (the Republic of)
- Lee, Yu ho, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea (the Republic of)
- Lee, Hyeyeon, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea (the Republic of)
- Yang, Taeyoung, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea (the Republic of)
- Lee, Sangho, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Kyung Hee University, Seoul, Korea (the Republic of)
Background
Oxidative stress induced by chronic hyperglycemia is recognized as a significant mechanistic contributor to the development of diabetic kidney disease (DKD). Nonphagocytic nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) is a major source of reactive oxygen species (ROS) in many cell types and in the kidney tissue of diabetic animals. We designed this study to explore the therapeutic potential of chloroquine and amodiaquine for inhibiting mitochondrial Nox4 and diabetic tubular injury.
Methods
Human renal proximal tubular epithelial cells (hRPTCs) were cultured in high-glucose media (30 mM D-glucose), and diabetes was induced with streptozotocin (STZ, 50 mg/kg i.p. for 5 days) in male C57/BL6J mice. Chloroquine and amodiaquine were administered to the mice via intraperitoneal injection for 14 weeks.
Results
Chloroquine and amodiaquine inhibited mitochondrial Nox4 and increased mitochondrial mass in hRPTCs under high-glucose conditions. Reduced mitochondrial ROS production after treatment with the drugs resulted in decreased endoplasmic reticulum (ER) stress, suppressed inflammatory protein expression and reduced cell apoptosis in hRPTCs under high-glucose conditions. Notably, chloroquine and amodiaquine treatment diminished Nox4 activation and ER stress in the kidneys of STZ-induced diabetic mice. In addition, we observed attenuated inflammatory protein expression and albuminuria in STZ-induced diabetic mice after chloroquine and amodiaquine treatment.
Conclusion
We substantiated the protective actions of chloroquine and amodiaquine in diabetic tubulopathy associated with reduced mitochondrial Nox4 activation and ER stress alleviation. Further studies exploring the roles of mitochondrial Nox4 in the pathogenesis of DKD could suggest new therapeutic targets for patients with DKD.
Funding
- Government Support - Non-U.S.