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Kidney Week

Abstract: FR-PO1064

Single-Cell Sequencing Identifies Novel Activated Fibroblast Marker, Distal Spatial Tubular Injury Pattern, and Functionally Significant Nephrogenic Program Reactivation in Adult AKI-to-CKD Transition

Session Information

Category: CKD (Non-Dialysis)

  • 2303 CKD (Non-Dialysis): Mechanisms

Authors

  • Rudman-Melnick, Valeria, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
  • Devarajan, Prasad, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
Background

Examining kidney fibrosis is crucial for mechanistic understanding and developing targeted strategies against chronic kidney disease (CKD). Enduring fibroblast activation and tubular epithelial cell (TEC) injury and dedifferenriation are key CKD contributors. However, specific activated kidney fibroblast markers and mechanistic targets of renal parenchymal remodeling remain elusive.

Methods

scRNA-seq, thorough molecular analysis and TEC specific transgenic model were used to mechanistically dissect AKI-to-CKD progression in two clinically relevant UIR and UUO murine models.

Results

Advanced kidney injuries elicited three separate “secretory”, “contractile” and “vascular” fibroblast clusters. Gucy1a1 was validated as a novel marker selectively labelling three fibroblast populations. Also, we found robust and previously unrecognized distal nephron tubular segment (DNTS) injury in both models, while the surviving proximal tubules (PTs) showed restored transcriptional signature. Both models elicited failed repair TECs (frTECs) exhibiting decline of mature epithelial markers and elevation of stromal and injury genes, which shared transcriptional identity with DNTSs of the embryonic kidney. We also found a persistent nephrogenic signature, including Sox4 elevation previously reported by us in AKI, in the UIR and UUO DNTSs. Sox4 targeting using KspCreERT2 transgenic model revealed renoprotective effects of Sox4 DNTS specific ablation in the kidney fibrosis.

Conclusion

We identified Gucy1a1 as a novel kidney fibroblast specific marker and targeting Sox4 in DNTSs as a promising strategy to halt AKI-to-CKD progression. Our findings might advance understanding of and targeted intervention in fibrotic kidney disease.

Funding

  • NIDDK Support