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

Nina A van de Lest; Aimée E Bakker; Kyra L Dijkstra; Malu Zandbergen; Sharon A C Heemskerk; Ron Wolterbeek; Jan A Bruijn; Marion Scharpfenecker

doi:10.1016/j.ekir.2021.04.013

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

Kidney Int Rep. 2021 Apr 22;6(7):1939-1948. doi: 10.1016/j.ekir.2021.04.013. eCollection 2021 Jul.

Authors

Nina A van de Lest¹, Aimée E Bakker¹, Kyra L Dijkstra¹, Malu Zandbergen¹, Sharon A C Heemskerk¹, Ron Wolterbeek², Jan A Bruijn¹, Marion Scharpfenecker¹

Affiliations

¹ Department of Pathology, Leiden University Medical Center, Leiden, Netherlands.
² Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands.

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 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_AR) 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_AR, nephrin and 8-oxo-guanine, a DNA lesion caused by oxidative damage. Glomeruli with ET_AR-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_AR-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_AR-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_AR-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_AR 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.

Keywords: crosstalk; endothelin receptor A; focal segmental glomerulosclerosis; glomerular endothelial cells; oxidative stress; podocytes.