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Kidney Week

Abstract: SA-PO095

Mechanisms of Injury and Protection in Ischemic AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Campbell, Jillian R., Richard L Roudebush VA Medical Center, Indianapolis, Indiana, United States
  • Dominguez, Jesus H., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Troyer, Meagan R., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Kelly, Katherine J., Indiana University School of Medicine, Indianapolis, Indiana, United States
Background

AKI is frequent and deadly. Effective therapy is an unmet need. In experimental ischemia, we have shown rapid improvement in renal function and structure after therapy with extracellular vesicles (EV, exosomes) derived from kidney, when given 24 hours postischemia. We hypothesized that EV from platelets, a rich and readily available source, or from skin epithelia would be beneficial. Our hypothesis was not true, but the difference between therapeutic and ineffective EV allows exploration of injury/protection mechanisms in an unbiased manner.

Methods

Using an established model of ischemia/reperfusion, mechanism was examined using spatial transcriptomics.

Results

As in previous studies, serum creatinine and histological evidence of injury were improved within 24 hours of delivery of EV from tubular cells. Renal EV improved multiple pathways of injury with ∼68% of transcripts altered postischemia improved with renal EV, including known markers of injury, such as HAVCR1 (KIM1, figure). Spatial analyses showed multiple alterations in all tubular segments, leukocytes, endothelia, glomeruli and regions of the kidney. Multiple pathways of immune and oxidant-mediated injury, including neutrophil extracellular trap formation and complement, were significantly altered with ischemia and improved with renal, but not platelet or skin, EV. In addition, only renal EV corrected alterations in mRNA involved in the programatic steps of peptide synthesis, cellular senescence and renal cytochrome p450. The latter is relevant because, as in liver, renal cytochrome enzymes may serve to preserve endothelial function and renal perfusion following ischemia.

Conclusion

The specific restoration by renal EV is consistent with the hypothesis that renal EV upload new sets of renal molecular instructions that reset the injured kidney towards rapid restoration of function and structure.

Spatial distribution of KIM1 in postischemic kidneys. Expression levels of HAVCR1 (KIM1) overlaid upon hematoxylin and eosin stained sections are presented. Significantly less expression is seen with renal extracellular vesicle (EV, exosome) treatment as compared to EV from platelets (plt) or skin.

Funding

  • NIDDK Support