The Ku protein family regulates hyperglycemia-induced vascular endothelial cell inflammation by modulating P300 levels.

Abstract

Endothelial inflammation caused by hyperglycemia contributes to cardiovascular complications in patients with diabetes. Diabetic kidney injury (DKI) is one of the most significant manifestations of diabetes-related renal damage, encompassing both acute and early chronic kidney injury. DKI involves pathological mechanisms linked to inflammatory responses and early renal damage, which, if left unchecked, may progress to diabetic kidney disease. Previous research indicates that both P300 and Ese-1 play pivotal roles in hyperglycemia-induced endothelial inflammation. This study suggests that P300 modulates Ese-1 expression, promoting hyperglycemia-mediated vascular endothelial inflammation and thereby contributing to the occurrence and progression of DKI. Our findings revealed increased levels of tumor necrosis factor α (Tnf-α), p65 phosphorylation, and monocyte chemotactic proteins Mip-1β and Mip-2 in the kidney tissues of diabetic mice and hyperglycemic human renal glomerular microvascular endothelial cells (HRGECs). Additionally, hyperglycemia orchestrated endothelial inflammation through the upregulation of Ese-1 expression in vitro. Furthermore, P300 was found to be upregulated both in vitro and in vivo. Moreover, silencing P300 reduced hyperglycemia-induced inflammatory effects, which could be reversed by overexpressing Ese-1 in HRGECs. Further, P300 was observed to interact with the Ku protein family (Ku70/Ku86), which were downregulated in the kidney tissues of diabetic mice and hyperglycemic HRGECs. siKu70 and siKu86 intensified hyperglycemia-induced endothelial inflammation, an effect counteracted by P300 silencing. In essence, the Ku protein family interacts with P300 to modulate Ese-1 expression in HRGECs, thereby participating in hyperglycemia-induced endothelial inflammation.