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.
(© 2021 International Society of Nephrology. Published by Elsevier Inc.)