Histone H3 Serine 10 Phosphorylation Facilitates Endothelial Activation in Diabetic Kidney Disease
| Autor: | Veera Ganesh Yerra, Sri N. Batchu, Suzanne L. Advani, Youan Liu, Mitchell J. Hadden, Syamantak Majumder, Bridgit B. Bowskill, Laurette Geldenhuys, Tamadher A. Alghamdi, Andrew Advani, Ferhan S. Siddiqi |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Nitric Oxide Synthase Type III Receptors CCR2 Endocrinology Diabetes and Metabolism Kidney Glomerulus Vascular Cell Adhesion Molecule-1 030209 endocrinology & metabolism Endothelial activation Histones 03 medical and health sciences Histone H3 Mice 0302 clinical medicine Downregulation and upregulation Internal Medicine Animals Humans Diabetic Nephropathies Phosphorylation Protein kinase A Promoter Regions Genetic Regulation of gene expression Mice Knockout biology Chemistry Podocytes Endothelial Cells Cell biology 030104 developmental biology Histone Mitogen-activated protein kinase biology.protein Endothelium Vascular Signal Transduction |
| Zdroj: | Diabetes. 67(12) |
| ISSN: | 1939-327X |
| Popis: | The posttranslational histone modifications that epigenetically affect gene transcription extend beyond conventionally studied methylation and acetylation patterns. By examining the means by which podocytes influence the glomerular endothelial phenotype, we identified a role for phosphorylation of histone H3 on serine residue 10 (phospho-histone H3Ser10) in mediating endothelial activation in diabetes. Culture media conditioned by podocytes exposed to high glucose caused glomerular endothelial vascular cell adhesion protein 1 (VCAM-1) upregulation and was enriched for the chemokine CCL2. A neutralizing anti-CCL2 antibody prevented VCAM-1 upregulation in cultured glomerular endothelial cells, and knockout of the CCL2 receptor CCR2 diminished glomerular VCAM-1 upregulation in diabetic mice. CCL2/CCR2 signaling induced glomerular endothelial VCAM-1 upregulation through a pathway regulated by p38 mitogen-activated protein kinase, mitogen- and stress-activated protein kinases 1/2 (MSK1/2), and phosphorylation of H3Ser10, whereas MSK1/2 inhibition decreased H3Ser10 phosphorylation at the VCAM1 promoter. Finally, increased phospho-histone H3Ser10 levels were observed in the kidneys of diabetic endothelial nitric oxide synthase knockout mice and in the glomeruli of humans with diabetic kidney disease. These findings demonstrate the influence that histone protein phosphorylation may have on gene activation in diabetic kidney disease. Histone protein phosphorylation should be borne in mind when considering epigenetic targets amenable to therapeutic manipulation in diabetes. |
| Databáze: | OpenAIRE |
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