Novel Soluble ACE2 Protein Lowers Kidney Angiotensin II and Improves Kidney Function in a Syngeneic Mouse Model of Delayed Graft Function After Kidney Transplantation

Background: Delayed graft function (DGF) is a form of acute kidney injury (AKI) occurring post-kidney transplantation, which is associated with unfavorable graft outcomes. Ischemia-reperfusion injury (IRI) plays an important role in the pathogenesis of DGF. Clinical and experimental data suggest that overactivity of the renin angiotensin system (RAS) with increased angiotensin II contributes to the pathogenesis of IRI and DGF. Since Angiotensin Converting enzyme 2 (ACE2) dissipates angiotensin II, we investigated the use of a soluble bioengineered ACE2 protein, ACE2-618-ABD, in a mouse model of DGF to counter RAS overactivity and improve kidney function. Methods: Syngeneic kidney transplantation was performed on male c57bl6 mice. The donor kidney was extracted and stored for three hours at 4° °C to mimic cold ischemia prior to transplantation to the recipient. ACE2-618-ABD or PBS as vehicle control were administered 20 minutes before as well as 24 hrs after the surgery. Blood urea nitrogen (BUN), kidney ACE2, and kidney angiotensin II were measured as main end points. Results: In kidneys from mice with DGF, kidney ACE2 enzymatic activity and protein were reduced, and ACE2 protein was recovered in the urine in increased amounts. Kidney angiotensin II was increased in DGF and reduced by the administration of ACE2-618-ABD (Figure, left panel). BUN was significantly reduced as compared to transplanted animals receiving PBS (Figure, right panel). Conclusion: Administration of the soluble ACE2 protein, ACE2-618-ABD reduced kidney angiotensin II and improved kidney function in a mouse model of DGF. ACE2-618-ABD counters overactivity of the RAS by dissipating excess angiotensin II and may represent a promising strategy to prevent/attenuate DGF. Funding: NIDDK Support