title: Mitochondria-targeted peptide SS-31 attenuates renal injury via an antioxidant effect in diabetic nephropathy.
abstract: Oxidative stress is implicated in the pathogenesis of diabetic kidney injury. SS-31 is a mitochondria-targeted tetrapeptide that can scavenge reactive oxygen species (ROS). Here, we investigated the effect and molecular mechanism of mitochondria-targeted antioxidant peptide SS-31 on injuries in diabetic kidneys and mouse mesangial cells (MMCs) exposed to high-glucose (HG) ambience. CD-1 mice underwent uninephrectomy and streptozotocin treatment prior to receiving daily intraperitoneal injection of SS-31 for 8 wk. The diabetic mice treated with SS-31 had alleviated proteinuria, urinary 8-hydroxy-2-deoxyguanosine level, glomerular hypertrophy, and accumulation of renal fibronectin and collagen IV. SS-31 attenuated renal cell apoptosis and expression of Bax and reversed the expression of Bcl-2 in diabetic mice kidneys. Furthermore, SS-31 inhibited expression of transforming-growth factor (TGF)-β1, Nox4, and thioredoxin-interacting protein (TXNIP), as well as activation of p38 MAPK and CREB and NADPH oxidase activity in diabetic kidneys. In vitro experiments using MMCs revealed that SS-31 inhibited HG-mediated ROS generation, apoptosis, expression of cleaved caspase-3, Bax/Bcl-2 ratio, and cytochrome c (cyt c) release from mitochondria. SS-31 normalized mitochondrial potential (ΔΨm) and ATP alterations, and inhibited the expression of TGF-β1, Nox4, and TXNIP, as well as activation of p38 MAPK and CREB and NADPH oxidase activity in MMCs under HG conditions. SS-31 treatment also could reverse the reduction of thioredoxin (TRX) biologic activity and upregulate expression of thioredoxin 2 (TRX2) in MMCs under HG conditions. In conclusion, this study demonstrates a protective effect of SS-31 against HG-induced renal injury via an antioxidant mechanism in diabetic nephropathy.
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China;
authors.forename: Yanjuan
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Department of Human Anatomy, Hebei Medical University, Shijiazhuang, China; and.
authors.forename: Shuangcheng
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China;
authors.forename: Ming
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China.
authors.forename: Jinying
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China.
authors.forename: Yunzhuo
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China.
authors.forename: Chunyang
authors.initials: C
authors.lastname: Du
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China;
authors.forename: Haijiang
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China.
authors.forename: Caili
authors.initials: C
authors.lastname: Han
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Duan
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China yonghongshi@163.com.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005353:Fibronectins / Q000378:metabolism; D005947:Glucose; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D024141:Collagen Type IV; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D005353:Fibronectins; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; C445672:Txnip protein, mouse; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide; D051028:bcl-2-Associated X Protein; D013879:Thioredoxins; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose
keywords: SS-31 peptide; apoptosis; diabetic nephropathy; mitochondria; oxidative stress