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Kidney Week

Abstract: PO0627

A Novel Short ACE2 Variant Causes ACE Suppression and Fosters Ang 1-7 Formation in a Murine Model of CKD

Session Information

  • CKD Mechanisms - 2
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Gulua, Gvantca, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Wysocki, Jan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Schulze, Arndt, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Ye, Minghao, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Haney, Chad R., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Zhao, Ming, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Zhang, Zheng Jenny, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Batlle, Daniel, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

ACE2 is a monocarboxypeptidase that cleaves Ang II to form Ang-(1-7). It is a large molecule the administration of which leads to increased enzyme activity in plasma, but not in the urine or kidney tissue. We have developed a truncated form of ACE2 that has a longer half-life by fusing it with an Albumin-binding domain (ABD) and is still short enough to be filtered by the kidney. In this study we examined the impact of this novel variant of ACE2 on kidney RAS in a model of CKD.

Methods

We used a 5/6 Nephrectomy model in CD-1 mice. The ACE2-ABD was given 3 days post-ablation surgery and thereafter every 3-4 days (3 ug/g BW) for 5 weeks. Afterwards, mice were euthanized and kidneys collected for analyses of RAS components.

Results

Administration of ACE2-ABD resulted in increased plasma ACE2 activity (768 vs. 12 RFU/ul/hr, p<0.0001). In kidney lysates there was also an increase in ACE2 activity (32 vs. 22 RFU/ug protein/hr, p=0.03) and a decrease in ACE activity (7187 vs. 4006 RFU/ug protein/hr, p=0.0001). These changes in enzymatic activities were accompanied by a significant increase in kidney Ang-(1-7) (90 vs. 37 fmol/mg protein, p=0.0014) without a significant change in Ang II levels (272 vs. 299 fmol/mg protein). To verify the kidney uptake of our ACE2 variant SPECT/Micro-CT imaging was performed. After the injection of radiolabeled ACE2-ABD kidney uptake was clearly seen (red) (Figure).

Conclusion

A long-acting form of a short ACE2 variant fused with ABD given every 3-4 days resulted in sustained plasma ACE2 activity and an increase in kidney ACE2 activity associated with suppressed kidney ACE activity. These enzymatic changes provide a favorable kidney RAS profile with increased Ang-(1-7), which overall should be renoprotective.

Funding

  • NIDDK Support