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Kidney Week

Abstract: TH-OR04

Analysis of the Immune Cell Landscape Identifies Immunosenescence as a Therapeutic Target in Rhabdomyolysis-Induced AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Rao, Snigdha N., INSERM U1297, Toulouse, FRANCE, France
  • Saulnier-Blache, Jean Sébastien, INSERM U1297, Toulouse, FRANCE, France
  • Schanstra, Joost, INSERM U1297, Toulouse, FRANCE, France
  • Belliere, Julie, INSERM U1297, Toulouse, FRANCE, France
Background

Rhabdomyolysis (RM) accounts for 10% of the acute kidney injury (AKI) cases. The role of macrophages in the development of RM-AKI lesions has been clearly established, but a high resolution understanding of the changes in the immune landscape could help to improve targeted strategies.

Methods

Single-cell RNA sequencing was used in the murine glycerol-induced RM-AKI model to dissect the transcriptomic characteristics of CD45+ live cells sorted from kidneys 2 days after injury. A combination of senolytics (dasatinib and quercetin) was administered to mice exposed or not to RM-AKI.

Results

Unsupervised clustering of nearly 17,000 single-cell transcriptomes identified 7 known immune cell clusters. Sub-clustering of the mononuclear phagocyte cells (MPC), including monocytes, macrophages and dendritic cells, revealed 9 distinct cell sub-populations differently modified with RM. One macrophage cluster was particularly interesting since it behaved as a critical node in a trajectory connecting one MCHIIhigh cluster only present in control to 2 MCHIIlow clusters only present RM-AKI. Because this crucial cluster expressed senescence hallmark genes, the effect of combined dasatinib and quercetin (DQ) senolytics treatment was evaluated. DQ treatment in RM-AKI improved kidney function and blocked the known phenotypic switch from F4/80highCD11blow to F4/80lowCD11bhigh MPC.

Conclusion

scRNASeq identified novel renal myeloid subtypes after RM-AKI and unmasked a transition macrophage population affected by cellular senescence processes. This work provides a proof-of-concept that immunosenescence occurs during AKI and that senolytics deserve attention as potential nephroprotective drugs.