TY  - JOUR
AU  - Bock, Fabian
AU  - Shahzad, Khurrum
AU  - Wang, Hongjie
AU  - Stoyanov, Stoyan
AU  - Wolter, Juliane
AU  - Dong, Wei
AU  - Pelicci, Pier Giuseppe
AU  - Kashif, Muhammed
AU  - Ranjan, Satish
AU  - Schmidt, Simone
AU  - Ritzel, Robert
AU  - Schwenger, Vedat
AU  - Reymann, Klaus G
AU  - Esmon, Charles T
AU  - Madhusudhan, Thati
AU  - Nawroth, Peter P
AU  - Isermann, Berend
TI  - Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66Shc.
JO  - Proceedings of the National Academy of Sciences of the United States of America
VL  - 110
IS  - 2
SN  - 0027-8424
CY  - Washington, DC
PB  - National Acad. of Sciences
M1  - DZNE-2020-03088
SP  - 648-653
PY  - 2013
AB  - 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.
KW  - Analysis of Variance
KW  - Animals
KW  - Butyrates: pharmacology
KW  - Chromatin Immunoprecipitation
KW  - DNA Methylation: drug effects
KW  - DNA Primers: genetics
KW  - Diabetes Mellitus, Experimental: complications
KW  - Diabetic Nephropathies: drug therapy
KW  - Diabetic Nephropathies: etiology
KW  - Epigenetic Repression: drug effects
KW  - Gene Knockdown Techniques
KW  - Immunoblotting
KW  - Immunohistochemistry
KW  - Membrane Potential, Mitochondrial: drug effects
KW  - Mice
KW  - Mitochondria: drug effects
KW  - Mitochondria: metabolism
KW  - Podocytes: metabolism
KW  - Protein C: pharmacology
KW  - Reverse Transcriptase Polymerase Chain Reaction
KW  - Shc Signaling Adaptor Proteins: antagonists & inhibitors
KW  - Shc Signaling Adaptor Proteins: metabolism
KW  - Src Homology 2 Domain-Containing, Transforming Protein 1
KW  - Statistics, Nonparametric
KW  - Subcellular Fractions
KW  - Butyrates (NLM Chemicals)
KW  - DNA Primers (NLM Chemicals)
KW  - Protein C (NLM Chemicals)
KW  - Shc Signaling Adaptor Proteins (NLM Chemicals)
KW  - Shc1 protein, mouse (NLM Chemicals)
KW  - Src Homology 2 Domain-Containing, Transforming Protein 1 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:23267072
C2  - pmc:PMC3545757
DO  - DOI:10.1073/pnas.1218667110
UR  - https://pub.dzne.de/record/136766
ER  -