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  1. AU="Lanting, Linda L"
  2. AU=Koushik Nikhil S
  3. AU="Culhane, John"
  4. AU="Chippada, Appa Rao"
  5. AU="Hiroki Sato" AU="Hiroki Sato"
  6. AU="Al-Amer Eshraq"
  7. AU="Thanacoody, Ruben"
  8. AU="Lin, Chi-Wei"
  9. AU="Chidambaram, Vignesh"

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  1. Artikel ; Online: Anti-Inflammatory Role of MicroRNA-146a in the Pathogenesis of Diabetic Nephropathy.

    Bhatt, Kirti / Lanting, Linda L / Jia, Ye / Yadav, Sailee / Reddy, Marpadga A / Magilnick, Nathaniel / Boldin, Mark / Natarajan, Rama

    Journal of the American Society of Nephrology : JASN

    2015  Band 27, Heft 8, Seite(n) 2277–2288

    Abstract: Inflammation has a critical role in the pathogenesis of diabetic complications, including diabetic nephropathy (DN). MicroRNAs have recently emerged as important regulators of DN. However, the role of microRNAs in the regulation of inflammation during DN ...

    Abstract Inflammation has a critical role in the pathogenesis of diabetic complications, including diabetic nephropathy (DN). MicroRNAs have recently emerged as important regulators of DN. However, the role of microRNAs in the regulation of inflammation during DN is poorly understood. Here, we examined the in vivo role of microRNA-146a (miR-146a), a known anti-inflammatory microRNA, in the pathogenesis of DN. In a model of streptozotocin-induced diabetes, miR-146a(-/-) mice showed significantly exacerbated proteinuria, renal macrophage infiltration, glomerular hypertrophy, and fibrosis relative to the respective levels in control wild-type mice. Diabetes-induced upregulation of proinflammatory and profibrotic genes was significantly greater in the kidneys of miR-146a(-/-) than in the kidneys of wild-type mice. Notably, miR-146a expression increased in both peritoneal and intrarenal macrophages in diabetic wild-type mice. Mechanistically, miR-146a deficiency during diabetes led to increased expression of M1 activation markers and suppression of M2 markers in macrophages. Concomitant with increased expression of proinflammatory cytokines, such as IL-1β and IL-18, markers of inflammasome activation also increased in the macrophages of diabetic miR-146a(-/-) mice. These studies suggest that in early DN, miR-146a upregulation exerts a protective effect by downregulating target inflammation-related genes, resulting in suppression of proinflammatory and inflammasome gene activation. Loss of this protective mechanism in miR-146a(-/-) mice leads to accelerated DN. Taken together, these results identify miR-146a as a novel anti-inflammatory noncoding RNA modulator of DN.
    Mesh-Begriff(e) Animals ; Diabetic Nephropathies/etiology ; Inflammation/etiology ; Macrophages ; Mice ; MicroRNAs/physiology
    Chemische Substanzen MicroRNAs ; Mirn146 microRNA, mouse
    Sprache Englisch
    Erscheinungsdatum 2015-12-08
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1085942-1
    ISSN 1533-3450 ; 1046-6673
    ISSN (online) 1533-3450
    ISSN 1046-6673
    DOI 10.1681/ASN.2015010111
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Transforming growth factor-β-induced cross talk between p53 and a microRNA in the pathogenesis of diabetic nephropathy.

    Deshpande, Supriya D / Putta, Sumanth / Wang, Mei / Lai, Jennifer Y / Bitzer, Markus / Nelson, Robert G / Lanting, Linda L / Kato, Mitsuo / Natarajan, Rama

    Diabetes

    2013  Band 62, Heft 9, Seite(n) 3151–3162

    Abstract: Elevated p53 expression is associated with several kidney diseases including diabetic nephropathy (DN). However, the mechanisms are unclear. We report that expression levels of transforming growth factor-β1 (TGF-β), p53, and microRNA-192 (miR-192) are ... ...

    Abstract Elevated p53 expression is associated with several kidney diseases including diabetic nephropathy (DN). However, the mechanisms are unclear. We report that expression levels of transforming growth factor-β1 (TGF-β), p53, and microRNA-192 (miR-192) are increased in the renal cortex of diabetic mice, and this is associated with enhanced glomerular expansion and fibrosis relative to nondiabetic mice. Targeting miR-192 with locked nucleic acid-modified inhibitors in vivo decreases expression of p53 in the renal cortex of control and streptozotocin-injected diabetic mice. Furthermore, mice with genetic deletion of miR-192 in vivo display attenuated renal cortical TGF-β and p53 expression when made diabetic, and have reduced renal fibrosis, hypertrophy, proteinuria, and albuminuria relative to diabetic wild-type mice. In vitro promoter regulation studies show that TGF-β induces reciprocal activation of miR-192 and p53, via the miR-192 target Zeb2, leading to augmentation of downstream events related to DN. Inverse correlation between miR-192 and Zeb2 was observed in glomeruli of human subjects with early DN, consistent with the mechanism seen in mice. Our results demonstrate for the first time a TGF-β-induced feedback amplification circuit between p53 and miR-192 related to the pathogenesis of DN, and that miR-192-knockout mice are protected from key features of DN.
    Mesh-Begriff(e) Animals ; Blotting, Western ; Cells, Cultured ; Diabetic Nephropathies/genetics ; Diabetic Nephropathies/metabolism ; Immunohistochemistry ; Mice ; Mice, Knockout ; Mice, Mutant Strains ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Oligonucleotide Array Sequence Analysis ; Reverse Transcriptase Polymerase Chain Reaction ; Transforming Growth Factor beta/genetics ; Transforming Growth Factor beta/metabolism ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
    Chemische Substanzen MicroRNAs ; Mirn192 microRNA, mouse ; Transforming Growth Factor beta ; Tumor Suppressor Protein p53
    Sprache Englisch
    Erscheinungsdatum 2013-05-06
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 80085-5
    ISSN 1939-327X ; 0012-1797
    ISSN (online) 1939-327X
    ISSN 0012-1797
    DOI 10.2337/db13-0305
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: Epigenetic Histone Modifications Involved in Profibrotic Gene Regulation by 12/15-Lipoxygenase and Its Oxidized Lipid Products in Diabetic Nephropathy.

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

    Antioxidants & redox signaling

    2016  Band 24, Heft 7, Seite(n) 361–375

    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, ...

    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.
    Mesh-Begriff(e) 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
    Chemische Substanzen 12-15-lipoxygenase ; Histones ; Hydroxyeicosatetraenoic Acids ; Transforming Growth Factor beta ; Arachidonate 12-Lipoxygenase (EC 1.13.11.31) ; Arachidonate 15-Lipoxygenase (EC 1.13.11.33) ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43)
    Sprache Englisch
    Erscheinungsdatum 2016-03-01
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1483836-9
    ISSN 1557-7716 ; 1523-0864
    ISSN (online) 1557-7716
    ISSN 1523-0864
    DOI 10.1089/ars.2015.6372
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: Epigenetic histone H3 lysine 9 methylation in metabolic memory and inflammatory phenotype of vascular smooth muscle cells in diabetes.

    Villeneuve, Louisa M / Reddy, Marpadga A / Lanting, Linda L / Wang, Mei / Meng, Li / Natarajan, Rama

    Proceedings of the National Academy of Sciences of the United States of America

    2008  Band 105, Heft 26, Seite(n) 9047–9052

    Abstract: Diabetic patients continue to develop inflammation and vascular complications even after achieving glycemic control. This poorly understood "metabolic memory" phenomenon poses major challenges in treating diabetes. Recent studies demonstrate a link ... ...

    Abstract Diabetic patients continue to develop inflammation and vascular complications even after achieving glycemic control. This poorly understood "metabolic memory" phenomenon poses major challenges in treating diabetes. Recent studies demonstrate a link between epigenetic changes such as chromatin histone lysine methylation and gene expression. We hypothesized that H3 lysine-9 tri-methylation (H3K9me3), a key repressive and relatively stable epigenetic chromatin mark, may be involved in metabolic memory. This was tested in vascular smooth muscle cells (VSMC) derived from type 2 diabetic db/db mice. These cells exhibit a persistent atherogenic and inflammatory phenotype even after culture in vitro. ChIP assays showed that H3K9me3 levels were significantly decreased at the promoters of key inflammatory genes in cultured db/db VSMC relative to control db/+ cells. Immunoblotting demonstrated that protein levels of the H3K9me3 methyltransferase Suv39h1 were also reduced in db/db VSMC. Furthermore, db/db VSMC were hypersensitive to TNF-alpha inflammatory stimulus, which induced dramatic and sustained decreases in promoter H3K9me3 and Suv39h1 occupancy. Recruitment of corepressor HP1alpha was also reduced under these conditions in db/db cells. Overexpression of SUV39H1 in db/db VSMC reversed this diabetic phenotype. Conversely, gene silencing of SUV39H1 with shRNAs in normal human VSMC (HVSMC) increased inflammatory genes. HVSMC cultured in high glucose also showed increased inflammatory gene expression and decreased H3K9me3 at their promoters. These results demonstrate protective roles for H3K9me3 and Suv39h1 against the preactivated state of diabetic VSMC. Dysregulation of epigenetic histone modifications may be a major underlying mechanism for metabolic memory and sustained proinflammatory phenotype of diabetic cells.
    Mesh-Begriff(e) Animals ; Chromosomal Proteins, Non-Histone/metabolism ; Diabetes Mellitus/genetics ; Diabetes Mellitus/immunology ; Epigenesis, Genetic/drug effects ; Glucose/pharmacology ; Histones/metabolism ; Humans ; Immunologic Memory/drug effects ; Inflammation/genetics ; Lysine/metabolism ; Methylation/drug effects ; Methyltransferases/metabolism ; Mice ; Muscle, Smooth, Vascular/drug effects ; Muscle, Smooth, Vascular/pathology ; Myocytes, Smooth Muscle/drug effects ; Myocytes, Smooth Muscle/pathology ; Phenotype ; Promoter Regions, Genetic/genetics ; Protein Binding/drug effects ; Repressor Proteins/metabolism ; Tumor Necrosis Factor-alpha/pharmacology
    Chemische Substanzen Chromosomal Proteins, Non-Histone ; Histones ; Repressor Proteins ; Tumor Necrosis Factor-alpha ; heterochromatin-specific nonhistone chromosomal protein HP-1 (107283-02-3) ; SUV39H1 protein, human (EC 2.1.1.) ; Methyltransferases (EC 2.1.1.-) ; Glucose (IY9XDZ35W2) ; Lysine (K3Z4F929H6)
    Sprache Englisch
    Erscheinungsdatum 2008-06-25
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.0803623105
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel: Epigenetic histone H3 lysine 9 methylation in metabolic memory and inflammatory phenotype of vascular smooth muscle cells in diabetes

    Villeneuve, Louisa M / Reddy, Marpadga A / Lanting, Linda L / Wang, Mei / Meng, Li / Natarajan, Rama

    Proceedings of the National Academy of Sciences of the United States of America. 2008 July 1, v. 105, no. 26

    2008  

    Abstract: Diabetic patients continue to develop inflammation and vascular complications even after achieving glycemic control. This poorly understood "metabolic memory" phenomenon poses major challenges in treating diabetes. Recent studies demonstrate a link ... ...

    Abstract Diabetic patients continue to develop inflammation and vascular complications even after achieving glycemic control. This poorly understood "metabolic memory" phenomenon poses major challenges in treating diabetes. Recent studies demonstrate a link between epigenetic changes such as chromatin histone lysine methylation and gene expression. We hypothesized that H3 lysine-9 tri-methylation (H3K9me3), a key repressive and relatively stable epigenetic chromatin mark, may be involved in metabolic memory. This was tested in vascular smooth muscle cells (VSMC) derived from type 2 diabetic db/db mice. These cells exhibit a persistent atherogenic and inflammatory phenotype even after culture in vitro. ChIP assays showed that H3K9me3 levels were significantly decreased at the promoters of key inflammatory genes in cultured db/db VSMC relative to control db/+ cells. Immunoblotting demonstrated that protein levels of the H3K9me3 methyltransferase Suv39h1 were also reduced in db/db VSMC. Furthermore, db/db VSMC were hypersensitive to TNF-α inflammatory stimulus, which induced dramatic and sustained decreases in promoter H3K9me3 and Suv39h1 occupancy. Recruitment of corepressor HP1α was also reduced under these conditions in db/db cells. Overexpression of SUV39H1 in db/db VSMC reversed this diabetic phenotype. Conversely, gene silencing of SUV39H1 with shRNAs in normal human VSMC (HVSMC) increased inflammatory genes. HVSMC cultured in high glucose also showed increased inflammatory gene expression and decreased H3K9me3 at their promoters. These results demonstrate protective roles for H3K9me3 and Suv39h1 against the preactivated state of diabetic VSMC. Dysregulation of epigenetic histone modifications may be a major underlying mechanism for metabolic memory and sustained proinflammatory phenotype of diabetic cells.
    Sprache Englisch
    Erscheinungsverlauf 2008-0701
    Umfang p. 9047-9052.
    Erscheinungsort National Academy of Sciences
    Dokumenttyp Artikel
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    Datenquelle NAL Katalog (AGRICOLA)

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