KITLG Promotes Glomerular Endothelial Cell Injury in Diabetic Nephropathy by an Autocrine Effect

Diabetic nephropathy (DN) is an increasing threat to human health. The impact of hyperglycemia or its metabolites, advanced glycation end-products (AGEs), on glomerular endothelial cells (GECs) and their pathophysiologic mechanisms are not well explored. Our results reveal that AGEs increased the expression and secretion of the KIT ligand (KITLG) in GECs. Both AGEs and KITLG promoted endothelial-to-mesenchymal transition (EndoMT) in GECs and further increased the permeability of GECs through the AKT/extracellular-signal-regulated kinase pathway. Inhibition of KITLG's effects by imatinib prevented AGE-medicated EndoMT in GECs, supporting the belief that KITLG is a critical factor for GEC injury. We found higher KITLG levels in the GECs and urine of db/db mice compared with db/m mice, and urinary KITLG levels were positively correlated with the urinary albumin-to-creatinine ratio (ACR). Furthermore, type 2 diabetic patients had higher urinary KITLG levels than normal individuals, as well as urinary KITLG levels that were positively correlated with urinary ACR and negatively correlated with the estimated glomerular filtration rate. KITLG plays a pathogenic role in GEC injury in DN and might act as a biomarker of DN progression.

Automated summary

Diabetic nephropathy is a growing threat to human health. This study reveals that high glucose or its metabolites, AGEs, increase the expression and secretion of KITLG in glomerular endothelial cells (GECs), leading to endothelial-to-mesenchymal transition (EndoMT) and increased permeability. Inhibition of KITLG's effects prevents AGE-mediated EndoMT in GECs, suggesting its critical role in GEC injury. KITLG levels are found to be higher in GECs and urine of diabetic mice and type 2 diabetic patients, and are correlated with urinary albumin-to-creatinine ratio and estimated glomerular filtration rate. KITLG may serve as a biomarker for DN progression.