Endothelial ETAR expression is associated with podocyte injury and oxidative stress in patients with FSGS

Abstract Introduction The podocyte is thought to be the mainly affected cell type in focal segmental glomerulosclerosis (FSGS). However, recent studies have also indicated a role for glomerular endothelial cells and podocyte-endothelial cross-talk in FSGS development. An experimental model for podocyte injury showed that increased endothelin-1 (ET-1) signaling between podocytes and endothelial cells induces endothelial oxidative stress and subsequent podocyte loss. In the current study, we investigated endothelial endothelin receptor A (ETAR) expression in patients with FSGS and its association with podocyte injury and glomerular oxidative stress. Methods We selected 39 biopsies of patients with FSGS and 8 healthy control subjects and stained them for ETAR, nephrin and 8-oxo-guanine, a DNA lesion caused by oxidative damage. Glomeruli with ETAR-positive endothelium and with nephrin loss were scored and the 8-oxo-guanine positive glomerular area was measured. Results The mean percentage of glomeruli with ETAR-positive endothelial cells in patients with FSGS was higher compared to healthy control subjects (52% vs. 7%; p Conclusion Taken together, we show that ETAR is increased in glomerular endothelial cells of patients with FSGS and associated with podocyte damage and glomerular oxidative stress. These findings support the hypothesis that ET-1 signaling in glomerular endothelial cells contributes to disease development in patients with FSGS.