Echinochrome A Prevents Diabetic Nephropathy by Inhibiting the PKC-Iota Pathway and Enhancing Renal Mitochondrial Function in db/db Mice
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Published:2023-03-30
Issue:4
Volume:21
Page:222
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ISSN:1660-3397
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Container-title:Marine Drugs
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language:en
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Short-container-title:Marine Drugs
Author:
Pham Trong12, Nguyen To1, Yun Hyeong1, Vasileva Elena3ORCID, Mishchenko Natalia3ORCID, Fedoreyev Sergey3ORCID, Stonik Valentin3, Vu Thu2, Nguyen Huy2ORCID, Cho Sung4ORCID, Kim Hyoung1ORCID, Han Jin1ORCID
Affiliation:
1. Department of Physiology, Cardiovascular and Metabolic Disease Center, Smart Marine Therapeutic Center, College of Medicine, Inje University, Busan 47392, Republic of Korea 2. Faculty of Biology, University of Science, Vietnam National University, Hanoi 10000, Vietnam 3. G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch of the Russian Academy of Science, 690022 Vladivostok, Russia 4. Division of Cardiology, Department of Internal Medicine, Ilsan Paik Hospital, Cardiac & Vascular Center, College of Medicine, Inje University, Goyang 10380, Republic of Korea
Abstract
Echinochrome A (EchA) is a natural bioproduct extracted from sea urchins, and is an active component of the clinical drug, Histochrome®. EchA has antioxidant, anti-inflammatory, and antimicrobial effects. However, its effects on diabetic nephropathy (DN) remain poorly understood. In the present study, seven-week-old diabetic and obese db/db mice were injected with Histochrome (0.3 mL/kg/day; EchA equivalent of 3 mg/kg/day) intraperitoneally for 12 weeks, while db/db control mice and wild-type (WT) mice received an equal amount of sterile 0.9% saline. EchA improved glucose tolerance and reduced blood urea nitrogen (BUN) and serum creatinine levels but did not affect body weight. In addition, EchA decreased renal malondialdehyde (MDA) and lipid hydroperoxide levels, and increased ATP production. Histologically, EchA treatment ameliorated renal fibrosis. Mechanistically, EchA suppressed oxidative stress and fibrosis by inhibiting protein kinase C-iota (PKCι)/p38 mitogen-activated protein kinase (MAPK), downregulating p53 and c-Jun phosphorylation, attenuating NADPH oxidase 4 (NOX4), and transforming growth factor-beta 1 (TGFβ1) signaling. Moreover, EchA enhanced AMPK phosphorylation and nuclear factor erythroid-2-related factor 2 (NRF2)/heme oxygenase 1 (HO-1) signaling, improving mitochondrial function and antioxidant activity. Collectively, these findings demonstrate that EchA prevents DN by inhibiting PKCι/p38 MAPK and upregulating the AMPKα/NRF2/HO-1 signaling pathways in db/db mice, and may provide a therapeutic option for DN.
Funder
Korean government Korean government (the Ministry of Science and ICT, the Ministry of Health & Welfare
Subject
Drug Discovery,Pharmacology, Toxicology and Pharmaceutics (miscellaneous),Pharmaceutical Science
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