Endothelial Endothelin Receptor A Expression Is Associated With Podocyte Injury and Oxidative Stress in Patients With Focal Segmental Glomerulosclerosis

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 crosstalk 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 (ET(A)R) expression in patients with FSGS and its association with podocyte injury and glomerular oxidative stress. METHODS: We selected 39 biopsy samples of patients with FSGS and 8 healthy control subjects, and stained them for ET(A)R, nephrin and 8-oxo-guanine, a DNA lesion caused by oxidative damage. Glomeruli with ET(A)R-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 ET(A)R-positive endothelial cells in patients with FSGS was higher compared to that in healthy control subjects (52% vs. 7%; P < 0.001). The presence of glomerular ET(A)R-positive endothelium was strongly associated with nephrin loss both on the biopsy level (rho = 0.47; P < 0.01), as on the level of individual glomeruli (odds ratio = 2.0; P < 0.001). Moreover, glomeruli with ET(A)R-positive endothelium showed more 8-oxo-guanine−positive staining (1.9% vs. 2.4%; P = 0.037). Finally, 8-oxo-guanine positivity in glomeruli was associated with increased levels of proteinuria. CONCLUSION: Taking together our findings, we show that ET(A)R 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.