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000136766 037__ $$aDZNE-2020-03088
000136766 041__ $$aEnglish
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000136766 1001_ $$0P:(DE-HGF)0$$aBock, Fabian$$b0
000136766 245__ $$aActivated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66Shc.
000136766 260__ $$aWashington, DC$$bNational Acad. of Sciences$$c2013
000136766 264_1 $$2Crossref$$3online$$bProceedings of the National Academy of Sciences$$c2012-12-24
000136766 264_1 $$2Crossref$$3print$$bProceedings of the National Academy of Sciences$$c2013-01-08
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000136766 520__ $$aThe 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.
000136766 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
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000136766 650_7 $$2NLM Chemicals$$aButyrates
000136766 650_7 $$2NLM Chemicals$$aDNA Primers
000136766 650_7 $$2NLM Chemicals$$aProtein C
000136766 650_7 $$2NLM Chemicals$$aShc Signaling Adaptor Proteins
000136766 650_7 $$2NLM Chemicals$$aShc1 protein, mouse
000136766 650_7 $$2NLM Chemicals$$aSrc Homology 2 Domain-Containing, Transforming Protein 1
000136766 650_2 $$2MeSH$$aAnalysis of Variance
000136766 650_2 $$2MeSH$$aAnimals
000136766 650_2 $$2MeSH$$aButyrates: pharmacology
000136766 650_2 $$2MeSH$$aChromatin Immunoprecipitation
000136766 650_2 $$2MeSH$$aDNA Methylation: drug effects
000136766 650_2 $$2MeSH$$aDNA Primers: genetics
000136766 650_2 $$2MeSH$$aDiabetes Mellitus, Experimental: complications
000136766 650_2 $$2MeSH$$aDiabetic Nephropathies: drug therapy
000136766 650_2 $$2MeSH$$aDiabetic Nephropathies: etiology
000136766 650_2 $$2MeSH$$aEpigenetic Repression: drug effects
000136766 650_2 $$2MeSH$$aGene Knockdown Techniques
000136766 650_2 $$2MeSH$$aImmunoblotting
000136766 650_2 $$2MeSH$$aImmunohistochemistry
000136766 650_2 $$2MeSH$$aMembrane Potential, Mitochondrial: drug effects
000136766 650_2 $$2MeSH$$aMice
000136766 650_2 $$2MeSH$$aMitochondria: drug effects
000136766 650_2 $$2MeSH$$aMitochondria: metabolism
000136766 650_2 $$2MeSH$$aPodocytes: metabolism
000136766 650_2 $$2MeSH$$aProtein C: pharmacology
000136766 650_2 $$2MeSH$$aReverse Transcriptase Polymerase Chain Reaction
000136766 650_2 $$2MeSH$$aShc Signaling Adaptor Proteins: antagonists & inhibitors
000136766 650_2 $$2MeSH$$aShc Signaling Adaptor Proteins: metabolism
000136766 650_2 $$2MeSH$$aSrc Homology 2 Domain-Containing, Transforming Protein 1
000136766 650_2 $$2MeSH$$aStatistics, Nonparametric
000136766 650_2 $$2MeSH$$aSubcellular Fractions
000136766 7001_ $$0P:(DE-HGF)0$$aShahzad, Khurrum$$b1
000136766 7001_ $$0P:(DE-HGF)0$$aWang, Hongjie$$b2
000136766 7001_ $$0P:(DE-2719)2809920$$aStoyanov, Stoyan$$b3$$udzne
000136766 7001_ $$0P:(DE-HGF)0$$aWolter, Juliane$$b4
000136766 7001_ $$0P:(DE-HGF)0$$aDong, Wei$$b5
000136766 7001_ $$0P:(DE-HGF)0$$aPelicci, Pier Giuseppe$$b6
000136766 7001_ $$0P:(DE-HGF)0$$aKashif, Muhammed$$b7
000136766 7001_ $$0P:(DE-HGF)0$$aRanjan, Satish$$b8
000136766 7001_ $$0P:(DE-HGF)0$$aSchmidt, Simone$$b9
000136766 7001_ $$0P:(DE-HGF)0$$aRitzel, Robert$$b10
000136766 7001_ $$0P:(DE-HGF)0$$aSchwenger, Vedat$$b11
000136766 7001_ $$0P:(DE-2719)2740485$$aReymann, Klaus G$$b12$$udzne
000136766 7001_ $$0P:(DE-HGF)0$$aEsmon, Charles T$$b13
000136766 7001_ $$0P:(DE-HGF)0$$aMadhusudhan, Thati$$b14
000136766 7001_ $$0P:(DE-HGF)0$$aNawroth, Peter P$$b15
000136766 7001_ $$0P:(DE-HGF)0$$aIsermann, Berend$$b16$$eCorresponding author
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000136766 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545757
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