Post-translational modification of histone proteins epigenetically affects gene transcription. The histone modifications that have been most extensively linked to the development of diabetes complications are histone (de)methylation and (de)acetylation, whereas other modifications have been comparatively overlooked. Here, by examining the means by which podocytes may influence the glomerular endothelial phenotype, we identified a role for the phosphorylation of histone H3 on serine residue 10 (H3Ser10) in mediating endothelial activation in diabetes. Culture media conditioned by high glucose-exposed podocytes induced glomerular endothelial vascular cell adhesion molecule-1 (VCAM-1) upregulation and was enriched for the chemokine CCL2 in a JAK2-dependent manner. Antagonism of CCR2, the cognate receptor for CCL2, decreased the endothelial VCAM-1 upregulation that was induced either by conditioned medium or by recombinant CCL2, whereas CCR2 knockout mice exhibited diminished glomerular VCAM-1 upregulation when challenged by diabetes. Recombinant CCL2 induced glomerular endothelial VCAM-1 upregulation through a pathway mediated by p38 MAPK, its nuclear substrates MSK1/2 and subsequent H3Ser10 phosphorylation, which was enriched at the VCAM-1 promoter. H3Ser10 phosphorylation levels were elevated in the kidneys of streptozotocin-diabetic endothelial nitric oxide synthase knockout (STZ-eNOS-/-) mice and in the glomeruli of humans with diabetic kidney disease. Finally, treatment of STZ-eNOS-/- mice with an inhibitor of JAK2 decreased both urinary CCL2 excretion and renal H3Ser10 phosphorylation. Collectively, these findings indicate that histone phosphorylation promotes endothelial activation in diabetes. Histone protein phosphorylation should be set alongside other more canonical histone modifications when considering chromatin modifications that influence diabetic kidney disease and that may be amenable to therapeutic intervention.


T. Alghamdi: None. S. Batchu: None. M.J. Hadden: None. Y. Liu: None. B. Bowskill: None. L. Geldenhuys: None. F.S. Siddiqi: Research Support; Self; AstraZeneca. S. Majumder: None. A. Advani: Research Support; Self; AstraZeneca, Boehringer Ingelheim GmbH. Other Relationship; Self; Boehringer Ingelheim GmbH.

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