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Abstract: TH-PO183

Spatial Mapping of Mesangial Cell Proliferative Signatures in the Diabetic Kidney

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Melo ferreira, Ricardo, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Asghari, Mahla, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Phillips, Carrie L., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Parikh, Samir V., The Ohio State University Wexner Medical Center, Columbus, Ohio, United States
  • Barwinska, Daria, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Ferkowicz, Michael J., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Sabo, Angela R., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Sutton, Timothy A., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Cheng, Ying-Hua, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Rovin, Brad H., The Ohio State University Wexner Medical Center, Columbus, Ohio, United States
  • El-Achkar, Tarek M., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Dagher, Pierre C., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Kelly, Katherine J., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Eadon, Michael T., Indiana University School of Medicine, Indianapolis, Indiana, United States

Group or Team Name

  • KPMP
Background

The renal mesangium undergoes adaptations in diabetic kidney disease (DKD). These changes include proliferation, hypertrophy, and mesangiolysis that ultimately lead to Kimmelstein-Wilson nodule formation. Using human reference nephrectomy and diabetic biopsy tissue, we sought to define the molecular transition of the mesangial cell (MC) as it undergoes these processes, including the coordinated signals arising from nearby degenerative podocytes and maladaptive glomerular capillary endothelial cells (GCECs).

Methods

We delineated the mRNA signature of renal mesangial cell adaptations in a merged KPMP / HubMAP snRNAseq atlas of reference and DKD specimens (>200,000 nuceli). The related signatures and cell neighborhoods in which they are expressed were localized with Seurat 3.2.3 to specific glomeruli within reference (N=6) and diabetic (N=10) kidney specimens using spatial transcriptomics. Spatial transcriptomic spots were selected based on glomerular cell type composition, and clustered based on the proportion of cell type signature, defining neighborhoods. Differential expression and pathway analysis further defined the signature of the neighborhoods.

Results

Transcriptome analysis revealed genes associated with MC fate in DKD. With the clustering analysis, we identified MC neighborhoods which included injured podocytes and maladaptive endothelial cells, more abundant in diabetic samples (p<0.05). Pathways enriched for those clusters are associated with morphology and development, and response to hypoxia. The trajectory of these molecular features was compared to histopathologic features (mesangial expansion, nodularity) within the specimens.

Conclusion

These studies suggest the existence of a temporal and spatial trajectory for mesangial cells in the progression of DKD, and describe the unique milieu of the diabetic glomeruli.

Funding

  • NIDDK Support