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Abstract: PO0008

AKI in a Mouse Model of COVID-19: Therapeutic Potential of a Novel Soluble ACE2 Variant

Session Information

Category: Coronavirus (COVID-19)

  • 000 Coronavirus (COVID-19)

Authors

  • Hassler, Luise, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Wysocki, Jan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Tomatsidou, Anastasia, The University of Chicago, Chicago, Illinois, United States
  • Gula, Haley, The University of Chicago, Chicago, Illinois, United States
  • Nicolaescu, Vlad I., The University of Chicago, Chicago, Illinois, United States
  • Sharma, Isha, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Randall, Glenn, The University of Chicago, Chicago, Illinois, United States
  • Kanwar, Yashpal S., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Batlle, Daniel, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

We have previously shown that in the ischemia reperfusion model of AKI kidney ACE2 activity decreases and that the administration of a shorter soluble ACE2 variant markedly attenuates AKI in terms of GFR and kidney histology (Shirazi et al, ASN 2019). Here, we report the effect of a novel ACE2 variant designed to prevent/treat SARS-CoV-2 in transgenic k18-hACE2 mice infected with a lethal viral dose.

Methods

In a BSL-3 facility, transgenic k18-hACE2 mice were infected intranasally with 2×104 PFU SARS-CoV-2. ACE2 1-618-DDC-ABD was administered intranasally and intra-peritoneally 1 hour prior to viral challenge as well as 24 and 48 hours afterwards for a total of 3 doses. Infected control animals received PBS at the same time-points. Kidneys were removed from all animals and examined by light microscopy (LM) histologically and for apoptosis, using PAS and TUNEL staining, respectively.

Results

In mice infected with SARS-CoV-2, variable degrees of AKI were found by LM with the following features seen in the few most severe cases: proximal tubule brush border loss (black arrows, figure 1A and B), cytolysis (red arrow, figure 1A), tubular basement membrane disruption (blue arrows, figure 1A and B) and apoptosis (white arrows, figure 1A, B, D and E). In animals treated with ACE2 1-618-DDC-ABD, survival was near 100% and proximal tubular kidney injury was absent or markedly attenuated with less proximal tubule injury (figure 1C) and minimal apoptosis (figure 1F). Glomeruli appeared ischemic (figure 1B, green arrow) but otherwise normal without evidence of thrombosis.

Conclusion

Kidneys from a transgenic mouse susceptible to SARS-CoV-2 infection, like patients with COVID-19, displays variable degrees of proximal tubular injury suggesting that this model can be useful to study AKI in COVID-19. Mice that received soluble ACE2 1-618-DDC-ABD protein were essentially protected from AKI suggesting a potential preventative/therapeutic role for soluble ACE2 in this otherwise pharmacologically untreatable devastating disease.

Funding

  • Private Foundation Support