Kidney Week

Abstract: FR-PO0201

Exploratory Single-Cell Analysis Suggests Limited Pathway Convergence Across Metabolic Kidney Injury Models

Session Information

• Diabetic Kidney Disease: Metabolic, Mitochondrial, and Inflammatory Mechanisms
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Cardiovascular-Kidney-Metabolic Health

• 601 Cardiovascular-Kidney-Metabolic Health: Basic

Authors

• Gisch, Debora L., Indiana University School of Medicine, Indianapolis, Indiana, United States

Debora L. Gisch, PhD

• Myakala, Komuraiah, Georgetown University, Washington, District of Columbia, United States

Komuraiah Myakala, PhD

• Wang, Xiaoxin, Georgetown University, Washington, District of Columbia, United States

Xiaoxin Wang, PhD

• Yennapureddy, Soumya, Indiana University School of Medicine, Indianapolis, Indiana, United States

Soumya Yennapureddy, MS

• Cheng, Ying-Hua, Indiana University School of Medicine, Indianapolis, Indiana, United States

Ying-Hua Cheng, MD, PhD

• Melo Ferreira, Ricardo, Indiana University School of Medicine, Indianapolis, Indiana, United States

Ricardo Melo Ferreira, PhD

• Eadon, Michael T., Indiana University School of Medicine, Indianapolis, Indiana, United States

Michael T. Eadon, MD, FASN

• Levi, Moshe, Georgetown University, Washington, District of Columbia, United States

Moshe Levi, MD, MS, FASN

Background

Metabolic kidney injury reflects complex interactions among hyperglycemia, obesity, diet-induced stress, inflammation, and oxidative injury. However, these processes may affect kidney compartments differently depending on the disease model. We applied single cell pathway analysis to interrogate the models and identify cell type convergency and divergency pathway regulation across db/db and Western diet associated kidney injury.

Methods

Sixteen week old Lepr^db/db mice were compared with age matched db/m controls. In a parallel diet-induced model, 10 week old C57BL/6J mice were fed either a Western diet (WD) or low-fat diet (LFD) for 24 weeks to induce metabolic kidney stress. Kidney single-cell RNA sequencing (N=4) was analyzed across annotated cell types/states to compare db/db vs db/m and WD vs LFD. Differential expression was assessed using the Wilcoxon test, followed by fgsea Reactome enrichment. Significant pathways were shared in the same direction or opposite direction using adjusted P<0.05 and normalized enrichment score direction (NES).

Results

In cell type matched comparisons, 96 Reactome pathways were shared by db/db and WD in the same direction, and 175 were in the opposite direction (adj. P<0.05). This pattern was observed at cell type/state and condition levels. Same direction sharing occurred in selected epithelial, podocyte, fibroblast, lymphoid, and endothelial compartments. For example, respiratory transport and translation pathways were positively enriched in podocytes and proximal tubules of db/db and WD when compared to controls. Opposite direction pathways were concentrated in lymphoid cells and endothelium compartments. Particularly, cell death and apoptosis were increased in WD lymphoid cells, but were negative in db/db. In endothelial cells, electron transport and steroid metabolism increased in WD, while phospholipid metabolism increased in db/db. This suggests compartment specific differences between db/db and WD associated with metabolic stress.

Conclusion

This analysis suggests cell type specific metabolic and injury response patterns in the db/db and WD models. These findings raise the possibility that genetic diabetes and diet-induced metabolic stress produce distinct kidney transcriptomic responses and can inform adequate model selection.

Funding

• NIDDK Support