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Beneficial Effect of Chloroquine and Amodiaquine on Type 1 Diabetic Tubulopathy by Attenuating Mitochondrial Nox4 and Endoplasmic Reticulum Stress

Journal of Korean Medical Science 2020년 35권 36호 p.305 ~ 305
강준모, 이현섭, 김정현, 양동호, 정혜윤, 이유호, 김동진, 박선화, 성민지, 김재희, 안현주, 이상호, 이소영,
소속 상세정보
강준모 ( Kang Jun-Mo ) - CHA University CHA Bundang Medical Center Department of Internal Medicine
이현섭 ( Lee Hyun-Seob ) - Seoul National University Hospital Biomedical Research Institute
김정현 ( Kim Jung-Hyun ) - CHA University CHA Bundang Medical Center Department of Internal Medicine
양동호 ( Yang Dong-Ho ) - CHA University CHA Bundang Medical Center Department of Internal Medicine
정혜윤 ( Jeong Hye-Yun ) - CHA University CHA Bundang Medical Center Department of Internal Medicine
이유호 ( Lee Yu-Ho ) - CHA University CHA Bundang Medical Center Department of Internal Medicine
김동진 ( Kim Dong-Jin ) - Kyung Hee University School of Medicine Kyung Hee University Hospital at Gangdong Department of Internal Medicine
박선화 ( Park Seon-Hwa ) - Kyung Hee University School of Medicine Kyung Hee University Hospital at Gangdong Department of Internal Medicine
성민지 ( Sung Min-Ji ) - CHA University CHA Bundang Medical Center Department of Internal Medicine
김재희 ( Kim Jae-Hee ) - CHA University CHA Bundang Medical Center Department of Internal Medicine
안현주 ( An Hyun-Ju ) - CHA University CHA Bundang Medical Center Department of Internal Medicine
이상호 ( Lee Sang-Ho ) - Kyung Hee University School of Medicine Kyung Hee University Hospital at Gangdong Department of Internal Medicine
이소영 ( Lee So-Young ) - CHA University CHA Bundang Medical Center Department of Internal Medicine

Abstract


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 (CQ) and amodiaquine (AQ) 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 C57BL/6J mice. CQ and AQ were administered to the mice via intraperitoneal injection for 14 weeks.

Results: CQ and AQ 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, CQ and AQ 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 CQ and AQ treatment.

Conclusion: We substantiated the protective actions of CQ and AQ 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.

키워드

Amodiaquine; Chloroquine; Diabetic Tubulopathy; Endoplasmic Reticulum Stress; Mitochondria; Nox4

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