Abstract: FR-PO285
Single-Cell Sequencing Detects Enrichment of ESKD Biomarkers in Injured Proximal Tubule
Session Information
- Diabetic Kidney Disease: Basic - 1
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Wilson, Parker C., University of Pennsylvania Department of Pathology and Laboratory Medicine, Philadelphia, Pennsylvania, United States
- Ihara, Katsuhito, Joslin Diabetes Center, Boston, Massachusetts, United States
- Satake, Eiichiro, Joslin Diabetes Center, Boston, Massachusetts, United States
- Humphreys, Benjamin D., Division of Nephrology, Department of Medicine, Washington University in St. Louis, St Louis, Missouri, United States
- Krolewski, Andrzej S., Joslin Diabetes Center, Boston, Massachusetts, United States
Background
Diabetic kidney disease (DKD) leads to rapid decline in some patients, but there are no biomarkers to identify these individuals. Proteomics profiles hundreds to thousands of candidate biomarkers, but little is known about how DKD affects these proteins or the cell types they originate from. Here, we identify circulating proteins that predict progression to ESKD using high-throughput proteomics (see Ihara K et al. Kidney Week 2024). We integrate these data with a single-cell atlas from patients with DKD to determine which cell types express these proteins.
Methods
We measured plasma concentration of 455 proteins among 405 individuals with diabetes using the OLINK platform. Elevated concentration of 46 proteins at baseline associated with progression to ESKD after 7-15 years. Single nucleus RNA sequencing (snRNA-seq) from patients with DKD (Wilson et al. 2022) was evaluated for cell-specific expression of biomarkers using Seurat. We focused on injured proximal tubule cells that variably express HAVCR1 and VCAM1 because the abundance of this cell type has been associated with kidney function decline.
Results
snRNA-seq showed that 14 of 46 circulating proteins predictive of ESKD were overexpressed in injured proximal tubule cells, including 11 genes encoding apoptosis and TNF-related receptor proteins (Figure A). Cell-specific expression of these biomarkers was correlated with aggregate expression of 205 apoptosis pathway genes. Imputation was performed to mitigate the sparsity of snRNA-seq, which increased the correlation between circulating biomarker expression and apoptosis pathway genes (Figure B).
Conclusion
We hypothesize that injured proximal tubule cells are a significant source of circulating biomarkers that predict progression to ESKD in individuals with diabetes.
Funding
- NIDDK Support