Thioredoxin-interacting protein regulates lipid metabolism via Akt/mTOR pathway in diabetic kidney disease |
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| Institution: | 1. Department of Pathology, Hebei Medical University, Shijiazhuang, China;2. Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China;3. BGI-Shenzhen, Shenzhen, Guangdong, China;4. Laboratorical Center for Electron Microscopy, Hebei Medical University, Shijiazhuang, China;1. Department of Agricultural, Food & Nutritional Science, University of Alberta, Edmonton, Alberta T6G 2P5, Canada;2. Department of Obstetrics & Gynecology, University of Alberta, Edmonton, Alberta T6G 2P5, Canada;3. Department of Physiology, University of Alberta, Edmonton, Alberta T6G 2P5, Canada;4. Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta T6G 2P5, Canada;5. Women and Children’s Health Research Institute, University of Alberta, Edmonton, Alberta T6G 2P5, Canada;1. Regenerative Medicine Program and Spinal Cord Research Centre, Canada;2. Dept. Physiology and Pathophysiology, University of Manitoba, Winnipeg, Canada;3. Division of Neurodegenerative Disorders, St. Boniface Hospital Research, Winnipeg, Manitoba, Canada;4. Department of Pharmacology and Therapeutics, Faculty of Health Sciences, College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada;1. Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China;2. Department of Cardiology, Shanghai Ninth People''s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200011, China;3. China Medical University, Shenyang, Liaoning, 110011, China;4. School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China;1. Department of Veterinary Pathology, Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea;2. Laboratory of Histopathology, Department of Clinical Laboratory Science, Semyung University, Jecheon 27136, Republic of Korea;3. Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea;3. de Duve Institute, Université Catholique de Louvain, B-1200 Brussels, Belgium;4. WELBIO, B-1200 Brussels, Belgium;5. Brussels Center for Redox Biology, B-1050 Brussels, Belgium;6. Structural Biology Research Center, Vlaams Instituut voor Biotechnologie, B-1050 Brussels, Belgium;12. Université de Lorraine, Faculté de Pharmacie, 54000 Nancy, France |
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| Abstract: | Abnormal lipid metabolism contributes to the renal lipid accumulation, which is associated with diabetic kidney disease, but its precise mechanism remains unclear. The growing evidence demonstrates that thioredoxin-interacting protein is involved in regulating cellular glucose and lipid metabolism. Here, we investigated the effects of thioredoxin-interacting protein on lipid accumulation in diabetic kidney disease. In contrast to the diabetic wild-type mice, the physical and biochemical parameters were improved in the diabetic thioredoxin-interacting protein knockout mice. The increased renal lipid accumulation, expression of acetyl-CoA carboxylase, fatty acid synthase and sterol regulatory element binding protein-1, and phosphorylated Akt and mTOR associated with diabetes in wild-type mice was attenuated in diabetic thioredoxin-interacting protein knockout mice. Furthermore, thioredoxin-interacting protein knockout significantly increased the expression of peroxisome proliferator-activated receptor-α, acyl-coenzyme A oxidase 1 and carnitine palmitoyltransferaser 1 in diabetic kidneys. In vitro experiments, using HK-2 cells, revealed that knockdown of thioredoxin-interacting protein inhibited high glucose-mediated lipid accumulation, expression of acetyl-CoA carboxylase, fatty acid synthase and sterol regulatory element binding protein-1, as well as activation of Akt and mTOR. Moreover, knockdown of thioredoxin-interacting protein reversed high glucose-induced reduction of peroxisome proliferator-activated receptor-α, acyl-coenzyme A oxidase 1 and carnitine palmitoyltransferaser 1 expression in HK-2 cells. Importantly, blockade of Akt/mTOR signaling pathway with LY294002, a specific PI3K inhibitor, replicated these effects of thioredoxin-interacting protein silencing. Taken together, these data suggest that thioredoxin-interacting protein deficiency alleviates diabetic renal lipid accumulation through regulation of Akt/mTOR pathway, thioredoxin-interacting protein may be a potential therapeutic target for diabetic kidney disease. |
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| Keywords: | Diabetic nephropathy TXNIP Lipid accumulation Akt/mTOR SREBP-1 PPARα |
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