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Abstract: PO2157

Improvement in Albuminuria and Hypertension in Renin Transgenic Mice by a Novel Filterable Form of Angiotensin-Converting-Enzyme 2 with Prolonged Half-Life

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Wysocki, Jan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Schulze, Arndt, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Gulua, Gvantca, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Ye, Minghao, 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 converts angiotensin (Ang) II to Ang 1-7. Its large molecular size precludes it from being filtered by the kidneys. We have developed shorter forms of mouse(619 AA) and human ACE2(618 AA) that are filterable but, like the native ACE2, have a short(hours) half-life in vivo. We bio-engineered a fused protein using an albumin binding domain(ABD) and tested its long-lasting effects in mice transgenic for an unregulated secretion of Renin(Ren TgMK).

Methods

Short soluble mouse(m) and human(h) ACE2 variants were fused with Albumin-Binding Domain(ABD). In vivo pharmacokinetic was determined after i.v. and i.p. injection followed by repeated measurement of plasma ACE2 activity. Subsequently, m and h rACE2-ABD(2 mg/kg) were injected every 2-3 days i.p. to Ren TgMK mice. The endpoints included urinary albumin(ACR) and blood pressure.

Results

Administration of 619-ABD to ACE2KO mice resulted in detectability of urinary ACE2 activity which at the baseline was not detectable. Blocking proximal tubule (PT) reabsorption with L-lysine, further increased urinary ACE2 activity suggesting that the ABD-tagged ACE2 undergoes glomerular filtration and is taken up by PT. In WT mice, augmentation of plasma ACE2 activity could still be shown a week after administration. In Ren TgMK mice, both m and h ACE2-ABD markedly reduced SBP and ACR(Figure).

Conclusion

A shorter soluble ACE2 variant fused with ABD exhibits a prolonged half-life while maintaining full enzymatic activity. The protein is filterable and re-absorbable by the proximal tubule, thereby providing increased kidney ACE2 activity as well as circulating plasma ACE2 activity. Its efficacy was documented by reduced BP and ACR in Ren TgMK, a hypertensive model due to RAS activation. Thus, this novel ACE2 variant with extended half-life offers potential for treatment of kidney disease and hypertension.

Funding

  • NIDDK Support