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@ARTICLE{Bock:136766,
      author       = {Bock, Fabian and Shahzad, Khurrum and Wang, Hongjie and
                      Stoyanov, Stoyan and Wolter, Juliane and Dong, Wei and
                      Pelicci, Pier Giuseppe and Kashif, Muhammed and Ranjan,
                      Satish and Schmidt, Simone and Ritzel, Robert and Schwenger,
                      Vedat and Reymann, Klaus G and Esmon, Charles T and
                      Madhusudhan, Thati and Nawroth, Peter P and Isermann,
                      Berend},
      title        = {{A}ctivated protein {C} ameliorates diabetic nephropathy by
                      epigenetically inhibiting the redox enzyme p66{S}hc.},
      journal      = {Proceedings of the National Academy of Sciences of the
                      United States of America},
      volume       = {110},
      number       = {2},
      issn         = {0027-8424},
      address      = {Washington, DC},
      publisher    = {National Acad. of Sciences},
      reportid     = {DZNE-2020-03088},
      pages        = {648-653},
      year         = {2013},
      abstract     = {The coagulation protease activated protein C (aPC) confers
                      cytoprotective effects in various in vitro and in vivo
                      disease models, including diabetic nephropathy. The
                      nephroprotective effect may be related to antioxidant
                      effects of aPC. However, the mechanism through which aPC may
                      convey these antioxidant effects and the functional
                      relevance of these properties remain unknown. Here, we show
                      that endogenous and exogenous aPC prevents glomerular
                      accumulation of oxidative stress markers and of the
                      redox-regulating protein p66(Shc) in experimental diabetic
                      nephropathy. These effects were predominately observed in
                      podocytes. In vitro, aPC inhibited glucose-induced
                      expression of p66(Shc) mRNA and protein in podocytes (via
                      PAR-1 and PAR-3) and various endothelial cell lines, but not
                      in glomerular endothelial cells. Treatment with aPC reversed
                      glucose-induced hypomethylation and hyperacetylation of the
                      p66(Shc) promoter in podocytes. The hyperacetylating agent
                      sodium butyrate abolished the suppressive effect of aPC on
                      p66(Shc) expression both in vitro and in vivo. Moreover,
                      sodium butyrate abolished the beneficial effects of aPC in
                      experimental diabetic nephropathy. Inhibition of p66(Shc)
                      expression and mitochondrial translocation by aPC normalized
                      mitochondrial ROS production and the mitochondrial membrane
                      potential in glucose-treated podocytes. Genetic ablation of
                      p66(Shc) compensated for the loss of protein C activation in
                      vivo, normalizing markers of diabetic nephropathy and
                      oxidative stress. These studies identify a unique mechanism
                      underlying the cytoprotective effect of aPC. Activated PC
                      epigenetically controls expression of the redox-regulating
                      protein p66(Shc), thus linking the extracellular protease
                      aPC to mitochondrial function in diabetic nephropathy.},
      keywords     = {Analysis of Variance / Animals / Butyrates: pharmacology /
                      Chromatin Immunoprecipitation / DNA Methylation: drug
                      effects / DNA Primers: genetics / Diabetes Mellitus,
                      Experimental: complications / Diabetic Nephropathies: drug
                      therapy / Diabetic Nephropathies: etiology / Epigenetic
                      Repression: drug effects / Gene Knockdown Techniques /
                      Immunoblotting / Immunohistochemistry / Membrane Potential,
                      Mitochondrial: drug effects / Mice / Mitochondria: drug
                      effects / Mitochondria: metabolism / Podocytes: metabolism /
                      Protein C: pharmacology / Reverse Transcriptase Polymerase
                      Chain Reaction / Shc Signaling Adaptor Proteins: antagonists
                      $\&$ inhibitors / Shc Signaling Adaptor Proteins: metabolism
                      / Src Homology 2 Domain-Containing, Transforming Protein 1 /
                      Statistics, Nonparametric / Subcellular Fractions /
                      Butyrates (NLM Chemicals) / DNA Primers (NLM Chemicals) /
                      Protein C (NLM Chemicals) / Shc Signaling Adaptor Proteins
                      (NLM Chemicals) / Shc1 protein, mouse (NLM Chemicals) / Src
                      Homology 2 Domain-Containing, Transforming Protein 1 (NLM
                      Chemicals)},
      cin          = {AG Dityatev / AG Reymann},
      ddc          = {500},
      cid          = {I:(DE-2719)1310007 / I:(DE-2719)1310005},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:23267072},
      pmc          = {pmc:PMC3545757},
      doi          = {10.1073/pnas.1218667110},
      url          = {https://pub.dzne.de/record/136766},
}