ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

Please note that you are viewing an archived section from 2019 and some content may be unavailable. To unlock all content for 2019, please visit the archives.

Abstract: TH-PO008

A Novel Angiotensin-Converting Enzyme 2 Truncate Markedly Improves Ischemic AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Shirazi, Mina, Northwestern University Feinberg Medical School, Chicago, Illinois, United States
  • Wysocki, Jan, Northwestern University Feinberg Medical School, Chicago, Illinois, United States
  • Ye, Minghao, Northwestern University Feinberg Medical School, Chicago, Illinois, United States
  • Haney, Chad R., Northwestern University Feinberg Medical School, Chicago, Illinois, United States
  • Zhao, Ming, Northwestern University Feinberg Medical School, Chicago, Illinois, United States
  • Kanwar, Yashpal S., Northwestern University Feinberg Medical School, Chicago, Illinois, United States
  • Zhang, Zheng Jenny, Northwestern University Feinberg Medical School, Chicago, Illinois, United States
  • Batlle, Daniel, Northwestern University Feinberg Medical School, Chicago, Illinois, United States
Background

RAS is overactive in AKI and therefore RAS blockers could be beneficial. Their use, however, is usually avoided because of their hypotensive and hemodynamic effects. An alternative approach to blocking the formation or action of angiotensin II (Ang II) is to foster its degradation. ACE2 is a tissue enzyme that degrades Ang II to Ang 1-7. Due to its large size, native ACE2 is not filterable. We therefore used a novel ACE2 truncate (1-619) to test the therapeutic potential in a unilateral model of ischemia-reperfusion injury (IRI).

Methods

IRI was induced in C57 mice by clamping the left renal pedicle for 30 min. ACE2 1-619 or vehicle (PBS) was administered 20 min prior to, and 5-6 h and 30 h after IRI. Renal function and tubular injury were assessed 24h and 48h post IRI. Filtration and renal uptake of 1-619 was assessed by SPECT/CT imaging.

Results

In 1-619-treated mice, GFR was higher at 24h (103±16 vs. 63±11 µl/min, P<0.05) and 48h (93±22 vs 38±93 µl/min, P<0.01) post IRI as compared to vehicle mice. Consistent with a better preserved GFR, BUN and Cr were lower in the 1-619-treated group as compared to their vehicle counterparts at 24h and 48h post IRI. ACE2 1-619 attenuated injury to the renal tubules as reflected by an improved tubular injury score and reduced kidney NGAL at 48h post IRI compared to vehicle mice. SPECT/CT showed comparable parenchymal activity of infused 1-619 in a mouse subjected to IRI 24h prior to imaging and an Nx control mouse. ACE2 activity was increased in kidneys of 1-619-injected mice as compared to vehicle mice at 48h post IRI (66±4 vs. 46±3 RFU/µg protein/h, P<0.01).

Conclusion

We conclude that the use of our novel ACE2 truncate downregulates the kidney RAS and provides a preventative/therapeutic approach to attenuate AKI.

Funding

  • NIDDK Support