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Abstract: FR-PO145

Spatially Resolved Distal Convoluted Tubule Transcriptome of AKI

Session Information

  • AKI: Mechanisms - II
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Jung, Hyun Jun, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Gharaie, Sepideh, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Lee, Kyungho, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Lo, Emily K., Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Noel, Sanjeev, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Cahan, Patrick, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Rabb, Hamid, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Welling, Paul A., Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
Background

Injury and failed repair transcriptome profiles of the renal proximal tubule and the loop of Henle have highlighted potential drivers of Acute Kidney Injury (AKI) and AKI to CKD. However, it is not clear if AKI affects gene expression profiles of other renal tubules, and whether injury is manifested focally by cell-cell communication or uniformly by autonomous mechanisms. Recent biomarker analyses raise the possibility that the distal convoluted tubule (DCT) might be especially sensitive to injury. This study aims to unravel gene expression responses of the DCT in AKI with spatial resolution at genome-wide depth.

Methods

Single-cell RNA sequencing (scRNA-Seq) data of human AKI patients (n=4) with healthy individuals (n=5) were obtained from the Kidney Precision Medicine Project (KPMP) and analyzed using Seurat (4.0). The 10× Genomics Visium Spatial Gene Expression platform was used to corroborate the human data in a mouse model of ischemia-reperfusion injury (IRI, ischemia for 30min followed by reperfusion for 24h), and to create an anatomical map of gene expression changes with CellRanger (6.0.1) and Seurat (4.0).

Results

Analyses of the KPMP scRNA-Seq data sets revealed that AKI is associated with remarkable alterations in the DCT transcriptome. This included increased expression of known kidney injury marker genes, Secreted Phosphoprotein 1 (Spp1), Lipocalin 2 (Lcn2) and Clusterin (Clu). A significant reduction of Epithelial growth factor (Egf) was also observed, paralleling changes in the loop of Henle. DCT-specific genes were altered, including decreased expression of Parvalbumin (Pvalb) and increased expression of Splat-like transcription factor 3 (Sall3). Spatial transcriptome profiling revealed IRI in mice has similar effects on gene expression as AKI in humans, affecting two distinct DCT cell-enriched clusters in the cortex, corresponding to early and late DCT. IRI affected the DCT transcriptome uniformly throughout the cortex.

Conclusion

In conclusion, the DCT transcriptome is especially sensitive to ischemic injury, exhibiting a unique injury-repair signature. The uniform change in gene expression across all DCT populations throughout the cortex suggests a cell-autonomous injury mechanism.

Funding

  • NIDDK Support