Abstract: FR-PO255
Spatially Resolved Transcriptomic Profiling of Diabetic Kidney Disease with Stepwise Analysis by Clinical Severity
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
- Oh, Jae-ik, Seoul National University Hospital, Jongno-gu, Seoul, Korea (the Republic of)
- Ku, Hyunah, Seoul National University College of Medicine, Jongno-gu, Seoul, Korea (the Republic of)
- Park, Sehoon, Seoul National University Hospital, Jongno-gu, Seoul, Korea (the Republic of)
- Kim, Dong Ki, Seoul National University College of Medicine, Jongno-gu, Seoul, Korea (the Republic of)
Background
Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease worldwide. Using spatial transcriptomics, we investigated glomerular and tubulointerstitial gene expression profiles in DKD to uncover novel insights for potential biomarkers.
Methods
Spatial transcriptomic profiling using GeoMx was performed on FFPE kidney biopsy specimens from 26 DKD patients and 10 control samples collected from donor kidney biopsy. We configured 73 glomerular and 77 tubulointerstitial ROIs from DKD samples. We compared the gene expression levels of DKD samples with the controls using DESeq2, and performed linear regression analysis for DKD samples categorized as follows, proceeding in the order: 1) random UPCr < 3g/g & eGFR≥60, 2) UPCr≥3 & eGFR≥60, 3) UPCr≥3 & eGFR<60. Gene ontology (GO) annotation was performed using EnrichR and ToppGene, and DEG interactions were mapped with STRING.
Results
The STAT family, VCAM1, TGFB family, and VEGF family, all well known to be associated with DKD, appeared as significant DEGs and showed a significant trend in linear regression analysis (p-value < 0.05).
In the tubulointerstitium, 1519 genes showed a negative correlation with worsening proteinuria and eGFR, including metallothionein gene family members (MT1F, MT1H, MT1X) known to mediate SFN renal protection fromd diabetes. G protein-coupled receptor activity and voltage-gated channel activity were among the top enriched GO terms.
In the glomeruli, 153 genes showed a positive correlation with worsening proteinuria and eGFR, including SREBF1 and PARL, which are associated with mitophagy regulation. This suggests that a PARL inhibitor may help prevent DKD progression by promoting efficient removal of damaged mitochondria from hyperglycemic conditions. Ribosomal subunits and collagen-containing extracellular matrix were among the top enriched GO terms.
Conclusion
Our study identifies potential therapeutic targets for DKD, supported by consistent trends observed in linear regression analysis. Especially, our findings suggest the potential clinical significance of targeting PARL in DKD.