Abstract: SA-PO0740
Glomerular Endothelial Rarefaction Associated with Hypoxic Neutrophils Marks Renal Pathology Activity in Lupus Nephritis
Session Information
- Glomerular Diseases: Profiling Through Multiomics
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Biswas, Aalekhya, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Mohan, Chandra, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Appalaneni, Rohith, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Cai, Qi, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Truong, Luan D., Houston Methodist, Houston, Texas, United States
- Saxena, Ramesh, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Surya, Vishal, University of Houston, Houston, Texas, United States
- Srinivasan, Vishal Akash A, University of Houston, Houston, Texas, United States
- Louis Sam Titus, Anto Sam Crosslee, University of Houston, Houston, Texas, United States
- Chen, Shu-Hsia, Houston Methodist, Houston, Texas, United States
Background
Hypoxia contributes to lupus nephritis (LN) pathology, yet its spatial distribution and immune implications in renal tissue are poorly defined.
Methods
12-plex Cyclic Immunofluorescence spatial proteomics (PhenoCycler-Fusion) was performed on renal biopsies from 6 LN patients and 6 controls, targeting HIF-1α, and immune/glomerular/tubular markers. Urinary MPO and proteinase 3 were assayed by ELISA.
Results
Compared to control glomeruli, LN glomeruli exhibited significant upregulation of HIF-1α expressing CD68+ve macrophages and CD66+ve neutrophils, associated with diffuse peri-nuclear staining for myeloperoxidase (MPO), suggestive of heightened NETosis, as well as N2 reparative neutrophils (Fig. 1). Spatial transcriptomic analysis in an independent LN cohort confirmed the correlation between glomerular hypoxia and NET formation. The renal pathology Activity Index (AI) was highly correlated with hypoxic neutrophil count (r=0.99) and the degree of glomerular endothelial rarefaction, marked by loss of endothelial cells, and capillary lengths, junctions/branching. Urinary neutrophil cargo and NET proteins, MPO and proteinase 3, were elevated in active LN.
Conclusion
We posit that glomerular endothelial cell damage leads to hypoxia in LN, resulting in hypoxic, reparative myeloid cells and neutrophil NETosis, while the latter has been linked to downstream inflammation and in situ trapping of anti-nuclear antibodies in LN. These glomerular events underpin high renal pathology activity, but may pave the path towards irreversible damage in LN.
Fig. 1: HIF1 expression in immune cells from LN biopsies: