title: Thioredoxin-interacting protein regulates lipid metabolism via Akt/mTOR pathway in diabetic kidney disease.
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.
authors: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China. Electronic address: duchunyang55@163.com.
authors: Chunyang
authors: C
authors: Du
authors: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China.
authors: Ming
authors: M
authors: Wu
authors: BGI-Shenzhen, Shenzhen, Guangdong, China.
authors: Huan
authors: H
authors: Liu
authors: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China. Electronic address: renyunzhuo1978@163.com.
authors: Yunzhuo
authors: Y
authors: Ren
authors: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China.
authors: Yunxia
authors: Y
authors: Du
authors: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China.
authors: Haijiang
authors: H
authors: Wu
authors: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China.
authors: Jinying
authors: J
authors: Wei
authors: BGI-Shenzhen, Shenzhen, Guangdong, China.
authors: Chuxin
authors: C
authors: Liu
authors: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China.
authors: Fang
authors: F
authors: Yao
authors: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China.
authors: Hui
authors: H
authors: Wang
authors: Laboratorical Center for Electron Microscopy, Hebei Medical University, Shijiazhuang, China.
authors: Yan
authors: Y
authors: Zhu
authors: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China. Electronic address: duanhj999@163.com.
authors: Huijun
authors: H
authors: Duan
authors: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China. Electronic address: yonghongshi@163.com.
authors: Yonghong
authors: Y
authors: Shi
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D054890:Fatty Acid Synthase, Type I / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing; D005947:Glucose / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D005227:Fatty Acids; D047493:PPAR alpha; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; C445672:Txnip protein, mouse; D013879:Thioredoxins; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C000588423:ACACA protein, human; D000103:Acetyl-CoA Carboxylase; D005947:Glucose
keywords: Akt/mTOR; Diabetic nephropathy; Lipid accumulation; PPARα; SREBP-1; TXNIP