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

• Published in: International journal of molecular sciences Vol. 23; no. 19; p. 11723
• Main Authors: Huang, Jiun-Chi, Chen, Szu-Chia, Chang, Wei-An, Hung, Wei-Wen, Wu, Ping-Hsun, Wu, Ling-Yu, Chang, Jer-Ming, Hsu, Ya-Ling, Tsai, Yi-Chun
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 03.10.2022; MDPI
• Subjects: Age; Biomarkers; Diabetes; Diabetic nephropathy; Endothelium; Glucose; Hyperglycemia; Inhibitor drugs; Kidney diseases; Kinases; Metabolites; Permeability; Phosphorylation; Proteins
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms231911723

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.