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Abstract: PO1661

Spatially Resolved Analysis of Glomerular Structures in Alport Syndrome and FSGS

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Perin, Laura, Children's Hospital of Los Angeles, Los Angeles, California, United States
  • Soloyan, Hasmik, Children's Hospital of Los Angeles, Los Angeles, California, United States
  • Cravedi, Paolo, Mount Sinai Health System, New York, New York, United States
  • Salem, Fadi E., Mount Sinai Health System, New York, New York, United States
  • Angeletti, Andrea, Universita di Bologna, Bologna, Emilia-Romagna, Italy
  • Sedrakyan, Sargis, Children's Hospital of Los Angeles, Los Angeles, California, United States
Background

Many transcriptomics studies highlighted the molecular mechanism underlying glomerular diseases, but very little is known about interglomerular heterogeneity and how each glomerular is affected during progressive CKD. Using Spatial transcriptomics, which allows the characterization of the gene expression based on morphological context, we showed important differences between glomeruli of Alport Syndrome (AS) and FSGS patients and defined the interactive gene networks involved in glomerulus damage using healthy glomeruli as reference.

Methods

Using the Nanostring GeoMX Digital Spatial Profiling (DSP, Whole Transcriptomic Atlas) we generated spatial maps of gene expression of human AS (COL4A5 and COL4A$) and FSGS glomeruli (both males and females) and compared them to age-matched healthy controls. A total of 90 regions of interest were selected. After data QC and Q3 normalization, data were analyzed using different platforms and integrated with histopathology assessment.

Results

Data distinguished genes associated with podocyte, glomerular endothelial and mesangial cell phenotype. Unsupervised clustering and dimensionality reduction analysis showed clear differences between not only diseased and normal glomeruli (which presented homogeneous gene expression profile), but also between glomeruli of AS vs FSGS. Though glomeruli of AS and FSGS were histologically similar within each sample, they presented different transcriptomics profiles (for instance, while oxidative phosphorylation, focal adhesions were common to all gloms in AS, Apelin, PI3K-Akt, and Hippo signaling were unique to only a few glomeruli). Marked differences between males and females were observed in both AS and FSGS glomeruli (sheer stress and leukocyte transendothelial migration was more typical in AS male than female, while insulin signaling was only present in AS female. Similar heterogeneity patterns were observed in FSGS). In contrast to FSGS, AS were more enriched for genes associated with TCA cycle, protein processing in the ER, and neurotrophin signaling.

Conclusion

DSP revealed significant interglomerular heterogeneity in AS and FSGS regardless of age and gender leading to the discovery of pathways defining disease phenotypes at single glomerulus level. These preliminary data using DSP may allow the discovery of potential new therapeutic targets for CKD patients.

Funding

  • NIDDK Support