Abstract: TH-PO331

Intravenous Exosomes Decrease Apoptotic Cell Death Following Rat Ischemic Renal Injury

Session Information

Category: Acute Kidney Injury

  • 002 AKI: Repair and Regeneration

Authors

  • Dominguez, Jesus H., VAMC, Indianapolis, Indiana, United States
  • Dominguez, James M., Indiana University, Indianapolis, Indiana, United States
  • Kelly, Katherine J., Indiana University, Indianapolis, Indiana, United States
Background

In acute kidney injury with ischemia (AKI), multiple, redundant pathways promote inflammation, sustained ischemia tubular cell death. The most common interpretation of cell death in AKI is by necrosis. However, death by apoptosis is an important process that may evolve over longer time after the initial injury. There is no treatment that can prevent the implementation of the dying process in AKI.

Methods

We infused renal tubular cells to treat two rat models of AKI: SD rats (given rat kidney exosomes) and Nude rats (NR) (given normal human kidney exosomes) subjected to 50 min of bilateral renal ischemia. Cells were given 24 and 48 hrs post-ischemia, and prevented injury after 6 days. The broad benefit of a few donor renal cells led to the hypothesis that their exosomes (EX) are the therapeutic effector.

Results

Hence, we infused EX from renal cells, 24 and 48 hrs post-ischemia. In ischemic NR, renal apoptosis was 4.4 fold higher in untreated AKI, as compared to sham controls, and it was prevented by EX, n = 5-4, p <0.05, for all. Equally ischemic SD showed upregulation of renal pro-apoptosis transcripts, casp4, casp8, fas, apaf1, bak, bax, p53 and TRAIL, fold increase 2.7, 2.1, 2.86, 2.05, 1.84, 1.43, 1.53 and 1.91 fold, respectively, and these were blunted by EX treatment, n = 5, p <0.05 for all. Ischemia also activated the anti-apoptotic genes bag2, birc 3 and birc5, 1.8, 3.5 and 3.1 fold, respectively, and EX suppressed this activation as well, p <0.05. Renal function and structure was markedly compromised after 6 days in untreated AKI. In contrast, EX treatment protected renal function and structure to a level similar to that of sham control rats in both sets.

Conclusion

We conclude, the apoptotic transcriptome is stimulated in untreated AKI, promoting renal apoptosis after 24 hrs of the initial injury. The concurrent activation of anti-apoptosis genes is not sufficient to reverse the apoptotic process triggered by AKI. EX prevented ischemic renal apoptosis by interfering with pro and anti-apoptotic activation, and prevented long-term functional and structural renal compromise. The 24 hour lag time after injury is an opportunity for intervention with EX intravenous infusions in AKI.

Funding

  • NIDDK Support