Kidney Week

Abstract: TH-PO1059

Altered Podocyte-Endothelial Cross-Talk and Increased Oxidative Stress in Patients with FSGS

Session Information

• Glomerular Diseases: Podocyte Biology - I
  November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1204 Podocyte Biology

Authors

• Van de Lest, Nina A., Leiden University Medical Center, Dept.Pathology, Leiden, Netherlands

Nina A. Van de Lest,

• Zandbergen, Malu, Leiden University Medical Center, Dept.Pathology, Leiden, Netherlands

Malu Zandbergen,

• Wolterbeek, Ron, Leiden University Medical Center, Leiden, Netherlands

Ron Wolterbeek,

• Bruijn, Jan A., Leiden University Medical Center, Dept.Pathology, Leiden, Netherlands

Jan A. Bruijn,

• Scharpfenecker, Marion, Leiden University Medical Center, Dept.Pathology, Leiden, Netherlands

Marion Scharpfenecker,

Background

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 for changes in crosstalk between these cells and podocytes in the development of FSGS. In an animal model for FSGS, it has been shown that endothelin-1 (ET-1) production by podocytes induces oxidative stress in endothelial cells, which subsequently induces podocyte loss. In this study, we investigated ET-1 signalling and associated oxidative stress and podocyte loss in patients with FSGS.

Methods

We selected 42 biopsies of patients with FSGS and 8 healthy controls and stained them for the endothelin receptor A (ET_AR) and nephrin. The number of glomeruli with ET_AR-positive endothelium and of glomeruli with nephrin loss were scored. In addition, FSGS patients and 10 protocol transplantation biopsies without specific pathology were stained for 8-OXO-G to indicate oxidative stress. Glomerular 8-OXO-G positivity was measured using ImageJ.

Results

In patients with FSGS, the mean percentage of glomeruli with ET_AR-positive endothelial cells was higher compared to healthy controls (52% vs. 7%; p<0.001). Also nephrin loss was observed in glomeruli of patients with FSGS. The percentage of glomeruli with ET_AR-positive endothelium correlated with the percentage of glomeruli with nephrin loss (rho=0.49; p<0.01). Moreover, the odds of having nephrin loss was higher for glomeruli with ET_AR-positive endothelium compared to ET_AR-negative glomeruli (OR: 2.0; p<0.0001). The median percentage of glomerular 8-OXO-G positivity was not significantly different between the two groups (0.90 vs 0.61; p=0.29). However, in patients with FSGS 8-OXO-G accumulation (median positivity ≥ 1.5) appeared to be more frequent compared to controls (40% vs 10%; p=0.07). Moreover, glomeruli with ET_AR-positive endothelium showed more 8-OXO-G positive staining (1.8 vs 2.3; p=0.038).

Conclusion

Patients with FSGS have increased positivity of ET_AR in glomerular endothelial cells and endothelial ET_AR positivity correlates with the degree of podocyte damage. In addition, glomerular oxidative stress, as indicated by the presence of 8-OXO-G, is increased in a subset of patients with FSGS and 8-OXO-G levels are higher in glomeruli with ET_AR-positive endothelial cells.