title: Mitofusin 2 attenuates the histone acetylation at collagen IV promoter in diabetic nephropathy.
abstract: Extracellular matrix (ECM) increase in diabetic nephropathy (DN) is closely related to mitochondrial dysfunction. The mechanism of protective function of mitofusin 2 (Mfn2) for mitochondria remains largely unknown. In this study, the molecular mechanisms for the effect of Mfn2 on mitochondria and subsequent collagen IV expression in DN were investigated. Ras-binding-deficient mitofusin 2 (Mfn2-Ras(Δ)) were overexpressed in rat glomerular mesangial cells, and then the cells were detected for mitochondrial morphology, cellular reactive oxygen species (ROS), mRNA and protein expression of collagen IV with advanced glycation end-product (AGE) stimulation. Preliminary results reveal that the mitochondrial dysfunction and the increased synthesis of collagen IV after AGE stimulation were reverted by Mfn2-Ras(Δ) overexpression. Bioinformatical computations were performed to search transcriptional factor motifs in the promoter region of collagen IV. Three specific regions for TFAP2A binding were identified, followed by validation with chromatin immunoprecipitation experiments. Knocking down TFAP2A significantly decreased the TF binding in the first two regions and the gene expression of collagen IV. Furthermore, results reveal that Mfn2-Ras(Δ) overexpression significantly mitigated TFAP2A binding and also reverted the histone acetylation at Regions 1 and 2 after AGE stimulation. In streptozotocin-induced diabetic rats, Mfn2-Ras(Δ) overexpression also ameliorated glomerular mesangial lesions with decreased collagen IV expression, accompanied by decreased acetylation and TFAP2A binding at Region 1. In conclusion, this study highlights the pathway by which mitochondria affect the histone acetylation of gene promoter and provides a new potential therapy approach for DN.
authors.affiliation: Division of NephrologyWest China Hospital, Sichuan University, Chengdu, China.
authors.forename: Xuhua
authors.initials: X
authors.lastname: Mi
authors.affiliation: Division of NephrologyWest China Hospital, Sichuan University, Chengdu, China kidney123@163.com.
authors.forename: Wanxin
authors.initials: W
authors.lastname: Tang
authors.affiliation: Division of NephrologyWest China Hospital, Sichuan University, Chengdu, China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Chen
authors.affiliation: Division of NephrologyWest China Hospital, Sichuan University, Chengdu, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: Division of NephrologyWest China Hospital, Sichuan University, Chengdu, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Tang
mesh_terms: D000107:Acetylation; D000818:Animals; D024141:Collagen Type IV / Q000235:genetics* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D057890:Epigenomics; D020558:GTP Phosphohydrolases; D005786:Gene Expression Regulation / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000378:metabolism / Q000494:pharmacology; D006657:Histones / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D059372:Nucleotide Motifs; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D050656:Transcription Factor AP-2 / Q000378:metabolism; D024363:Transcription Initiation Site; D018631:ras Proteins / Q000378:metabolism
chemical_list: D024141:Collagen Type IV; D017127:Glycation End Products, Advanced; D006657:Histones; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C493673:TFAP2A protein, human; D050656:Transcription Factor AP-2; D020558:GTP Phosphohydrolases; C489710:Mfn2 protein, rat; D018631:ras Proteins
keywords: Mitofusin 2; acetylation; collagen; diabetic nephropathy; histone