ArticleProceedings of the National Academy of Sciences of the United States of America2013
Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66Shc.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.
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Who cites it
77 citing papers in PubMed, 142 citations in OpenAlex.
- Epigenetic and O-glycosylation regulation of p66Shc mitigates mitochondrial oxidative stress in aortic dissection.Theranostics · 2026Article
- P16-positive senescent cells promote DKD by the dysregulation of glycolysis and mitochondrial metabolism.Cell death discovery · 2025Article
- Renal aging and its consequences: navigating the challenges of an aging population.Frontiers in pharmacology · 2025Review
- Insulin-like growth factor-1 effects on kidney development in preterm piglets.Pediatric research · 2024Article
- Krüppel-like factor 2 is an endoprotective transcription factor in diabetic kidney disease.American journal of physiology. Cell physiology · 2024Review
- Coagulation Protease-Driven Cancer Immune Evasion: Potential Targets for Cancer Immunotherapy.Cancers · 2024Review
- Exploring the Gut-Mitochondrial Axis: p66Shc Adapter Protein and Its Implications for Metabolic Disorders.International journal of molecular sciences · 2024Review
- The p66International journal of molecular sciences · 2023Review
- Activated protein C modulates T-cell metabolism and epigenetic FOXP3 induction via α-ketoglutarate.Blood advances · 2023Article
- APC ameliorates idiopathic membranous nephropathy by affecting podocyte apoptosis through the ERK1/2/YB-1/PLA2R1 axis.Molecular and cellular biochemistry · 2023Article
- Redox regulation in diabetic kidney disease.American journal of physiology. Renal physiology · 2023Review
- The impact of oxidative stress-induced mitochondrial dysfunction on diabetic microvascular complications.Frontiers in endocrinology · 2023Review
- Reversal of the renal hyperglycemic memory in diabetic kidney disease by targeting sustained tubular p21 expression.Nature communications · 2022Article
- Activated Protein C Ameliorates Tubular Mitochondrial Reactive Oxygen Species and Inflammation in Diabetic Kidney Disease.Nutrients · 2022Article
- ER-Stress and Senescence Coordinately Promote Endothelial Barrier Dysfunction in Diabetes-Induced Atherosclerosis.Nutrients · 2022Article
- Article
- Mitochondrial Oxidative Stress and Cell Death in Podocytopathies.Biomolecules · 2022Review
- The Role of p66Shc in Diabetes: A Comprehensive Review from Bench to Bedside.Journal of diabetes research · 2022Review
- The role and mechanism of butyrate in the prevention and treatment of diabetic kidney disease.Frontiers in microbiology · 2022Review
- Protective Role of Activated Protein C against Viral Mimetic Poly(I:C)-Induced Inflammation.Thrombosis and haemostasis · 2021Article
17 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 7 institutions in 5 countries.
Funding
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.
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