Epigenetic Histone Modifications Involved in Profibrotic Gene Regulation by 12/15-Lipoxygenase and Its Oxidized Lipid Products in Diabetic Nephropathy

Hang Yuan; Marpadga A Reddy; Supriya Deshpande; Ye Jia; Jung Tak Park; Linda L Lanting; Wen Jin; Mitsuo Kato; Zhong Gao Xu; Sadhan Das; Rama Natarajan

doi:10.1089/ars.2015.6372

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Epigenetic Histone Modifications Involved in Profibrotic Gene Regulation by 12/15-Lipoxygenase and Its Oxidized Lipid Products in Diabetic Nephropathy

Authors: Hang Yuan ; Marpadga A Reddy ; Supriya Deshpande ; Ye Jia ; Jung Tak Park ; Linda L Lanting ; Wen Jin ; Mitsuo Kato ; Zhong Gao Xu ; Sadhan Das ; Rama Natarajan

Citation: ANTIOXIDANTS & REDOX SIGNALING, Vol.24(7) : 361-375, 2016-03

Journal Title: ANTIOXIDANTS & REDOX SIGNALING

ISSN: 1523-0864

Issue Date: 2016-03

MeSH: Animals ; Arachidonate 12-Lipoxygenase / genetics ; Arachidonate 12-Lipoxygenase / metabolism* ; Arachidonate 15-Lipoxygenase / genetics ; Arachidonate 15-Lipoxygenase / metabolism* ; Chromatin Immunoprecipitation ; Diabetes Mellitus, Experimental ; Diabetic Nephropathies / genetics* ; Diabetic Nephropathies / metabolism* ; Diabetic Nephropathies / pathology ; Diabetic Nephropathies / physiopathology ; Disease Models, Animal ; Epigenesis, Genetic* ; Fibrosis / genetics ; Gene Expression Regulation* / drug effects ; Gene Silencing ; High-Throughput Nucleotide Sequencing ; Histone-Lysine N-Methyltransferase / genetics ; Histone-Lysine N-Methyltransferase / metabolism ; Histones / genetics* ; Histones / metabolism ; Hydroxyeicosatetraenoic Acids / metabolism ; Hydroxyeicosatetraenoic Acids / pharmacology ; Lipid Metabolism* ; Mesangial Cells / drug effects ; Mesangial Cells / metabolism ; Mice ; Mice, Knockout ; Oxidation-Reduction ; Promoter Regions, Genetic ; Rats ; Transforming Growth Factor beta / metabolism ; Transforming Growth Factor beta / pharmacology

Abstract: Aims: Epigenetic mechanisms, including histone post-translational modifications and DNA methylation, are implicated in the pathogenesis of diabetic nephropathy (DN), but the mediators are not well known. Moreover, although dyslipidemia contributes to DN, epigenetic changes triggered by lipids are unclear. In diabetes, increased expression of 12/15-lipoxygenase (12/15-LO) enhances oxidized lipids such as 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], which promote oxidant stress, glomerular and mesangial cell (MC) dysfunction, and fibrosis, and mediate the actions of profibrotic growth factors. We hypothesized that 12/15-LO and its oxidized lipid products can regulate epigenetic mechanisms mediating profibrotic gene expression related to DN.

Results: 12(S)-HETE increased profibrotic gene expression and enrichment of permissive histone lysine modifications at their promoters in MCs. 12(S)-HETE also increased protein levels of SET7, a histone H3 lysine 4 methyltransferase, and promoted its nuclear translocation and enrichment at profibrotic gene promoters. Furthermore, SET7 (Setd7) gene silencing inhibited 12(S)-HETE-induced profibrotic gene expression. 12/15-LO (Alox15) gene silencing or genetic knockout inhibited transforming growth factor-β1 (TGF-β1)-induced expression of Setd7 and profibrotic genes and histone modifications in MCs. Furthermore, 12/15-LO knockout in mice ameliorated key features of DN and abrogated increases in renal SET7 and profibrotic genes. Additionally, 12/15-LO siRNAs in vivo blocked increases in renal SET7 and profibrotic genes in diabetic mice.

Innovation and conclusion: These novel results demonstrate for the first time that 12/15-LO-derived oxidized lipids regulate histone modifications associated with profibrotic gene expression in MCs, and 12/15-LO can mediate similar actions of TGF-β1 and diabetes. Targeting 12/15-LO might be a useful strategy to inhibit key epigenetic mechanisms involved in DN.