385-P: MDSC-Mediated Neutrophil Extracellular Traps–Based Targeting of Diabetic Vasculopathy—Dapagliflozin for Vascular Remodeling in Diabetic Nephropathy

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide, and its pathogenetic mechanism is closely associated with vascular endothelial dysfunction. Myeloid-derived suppressor cells (MDSCs) recently have been found to be participated in diabetic microangiopathy, especially DN, which can promote beneficial vascular remodeling by releasing neutrophil extracellular traps (NETs) and removing senescent vascular endothelium. Therefore, targeting MDSC-NETs may also be an important mechanism for dapagliflozin to ameliorate DN. Focusing on this mechanism, based on the KKay mice model of spontaneous DN, we combined phenotyping and electron microscopy to obtain the evidence that dapagliflozin was effective in ameliorating urine albumin creatine ratio and the structural damage of glomerular vascular endothelium.Then through immunohistochemistry, flow cytometry, quantitative cytokine antibody array, metabolomics, proteomics, and other multi-omics correlation analyses, to find that dapagliflozin significantly increased M-MDSC and PMN-MDSC levels in the peripheral blood of KKay mice. Dapagliflozin was found to improve glomerular endothelial function and hemodynamics by NETs-formatting, leukocyte transendothelial migration, complement and coagulation cascades, VEGF-JAK-STAT3 pathway, and reduced vascular-related pro-inflammatory cytokines such as CCL4, IL-22, IL23, TREM-1, CCL17, IGFBP5, and TGFb1. Meanwhile, dapagliflozin regulates the metabolism of amino acids and phospholipids represented by L-glutamine and phosphatidylcholine in renal tissues, attenuates the metabolic inflammatory state of glomerular endothelium, and promotes vascular repair and remodeling.