Kidney Week

Abstract: FR-PO286

Single-Cell Profiling of Peripheral Blood Mononuclear Cell Identifies Immune Populations Associated with Progression of Diabetic Kidney Disease

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

• Fu, Jia, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Jia Fu, MD, MS

• Sun, Zeguo, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Zeguo Sun

• Wen, Huei Hsun, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Huei Hsun Wen, MD, MS

• Chang, Dongyuan, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Dongyuan Chang, MD

• Mosoyan, Gohar, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Gohar Mosoyan, MS

• Lee, Kyung, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Kyung Lee, PhD, FASN

• Coca, Steven G., Icahn School of Medicine at Mount Sinai, New York, New York, United States

Steven G. Coca, DO, MS

• Nadkarni, Girish N., Icahn School of Medicine at Mount Sinai, New York, New York, United States

Girish N. Nadkarni, MD, MPH

• He, John Cijiang, Icahn School of Medicine at Mount Sinai, New York, New York, United States

John Cijiang He, MD, PhD, FASN

Background

Emerging evidence has highlighted the pivotal role of inflammation in the development and progression of DKD. Notably, TNF receptors have demonstrated notable associations with eGFR decline in both early and advanced DKD. However, to date, there has not been a comprehensive characterization of circulating immune cell phenotypes in DKD and their relationship with disease progression at the single-cell level.

Methods

In this study, we performed single-cell RNA sequencing of PBMCs from 12 patients, stratified based on high and low serum TNFR levels. Our aim was to discern immune cell subpopulations and their transcriptomic signatures associated with the DKD progression.

Results

By assessing the eGFR slope, serum levels of TNFR-1 and TNFR-2, we have discerned 12 patients demonstrating varying degrees of underlying DKD. Our scRNAseq analysis profiled 109,955 PBMCs, revealing TNFR1 and TNFR2 genes predominantly expressed on CD14 and CD16 monocytes. Circulating TNFR-1 levels correlated positively with monocyte population and negatively with T cells and dendritic cells, while TNFR-2 levels correlated negatively with dendritic cells and CD8 T cell proportion. Increased CD14 and CD16 monocytes and decreased plasmacytoid dendritic cells (pDCs)and CD4 T cells were observed to correlate with DKD progression. Profound alterations in circulatory immune cell signatures were noted, with more upregulated differential expressed genes (DEGs) in slowly progressed DKD and subsequent downregulated in advanced stages. These DEGs primarily involved in cytokine expression, immune-related pathways, apoptotic signaling, and response to IFN, suggesting potential immunomodulatory roles of elevated circulating TNFR in DKD activation. Additionally, important co-expressed genes with TNFR1 and TNFR2 implicated processes such as osteoclast differentiation, cytokine interaction, endocytosis, and MAPK pathways.

Conclusion

Our study utilized single-cell RNA sequencing of PBMCs to comprehensively profile immune cell dynamics in patients stratified by serum TNFR levels, revealing their intricate interplay in the progression of DKD. These findings provide valuable insights into potential immunomodulatory targets for therapeutic intervention in DKD.

Funding

• NIDDK Support