Histone H3 Serine 10 Phosphorylation Facilitates Endothelial Activation in Diabetic Kidney Disease

The posttranslational histonemodifications that epigenetically affect gene transcription extend beyond conventionally studied methylation and acetylation patterns. By examining the means by which podocytesinfluence the glomerular endothelial phenotype, we identified a role for phosphorylation of histone H3on serine residue 10 (phospho- histoneH3Ser10) in mediating endothelial activationin diabetes. Culture media conditioned by podocytesexposed to high glucose caused glomerular endothelial vascular cell adhesion protein1 ( VCAM-1) upregulation and was enriched for the chemokine CCL2. A neutralizing anti- CCL2antibody prevented VCAM-1upregulation in cultured glomerular endothelial cells, and knockout of the CCL2receptor CCR2diminished glomerular VCAM-1upregulation in diabetic mice. CCL2/ CCR2signaling induced glomerular endothelial VCAM-1upregulation 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- histoneH3Ser10 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 phosphorylationmay have on gene activation in diabetic kidney disease. Histone protein phosphorylationshould be borne in mind when considering epigenetic targets amenable to therapeutic manipulation in diabetes.