Novel Short ACE2 variant for Delayed Graft Function

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Project summary Delayed graft function (DGF) is a form of acute kidney injury clinically defined as the need for dialysis within one week of kidney transplantation. It affects up to 50% of deceased-donor kidney transplant recipients. Because of the organ shortage crisis, marginal or expanded criteria donor kidneys are increasingly considered even though these kidneys are at higher risk to develop DGF. Patients with DGF have a higher risk of allograft rejection and death. DGF is largely caused by acute proximal tubular injury induced by ischemia. There are no FDA-approved treatments available to date. Treatment or prevention of delayed graft function, therefore, poses an unmet clinical need and new approaches to prevent and attenuate DGF are urgently needed. In this proposal, we want to examine the preventative value of administering a shorter angiotensin converting enzyme 2 (ACE2) variant . We have preliminary data that a short mouse ACE2 variant protects against acute kidney injury (AKI) caused by ischemia reperfusion injury (IRI). As ischemia reperfusion injury is the driving force of DGF, we propose that a novel short human ACE2 variant can prevent and attenuate DGF. ACE2 is a tissue enzyme abundant in the kidneys that cleaves the amino acid phenylalanine to form Angiotensin (Ang) (1- 7) from Ang II (Ang (1-8)). In a genetic model of ACE2 deficiency, AKI induced by ischemia-reperfusion is aggravated and moreover a decrease in kidney ACE2 activity has been reported in AKI which leads to less formation of Ang 1-7 from Ang II. Therefore, there is a rationale for administering ACE2 to the kidney with AKI and by extension to prevent / attenuate DGF. We propose to examine the potential preventative / therapeutic effect of a novel human ACE2 variant which is shorter than the native soluble ACE2 and therefore filterable across the glomerular filtration barrier such that it can be taken up by the kidney proximal tubule where it fosters the degradation of Ang II and the formation of Ang 1-7. With this approach, the formation of Ang II continues, such that the systemic and renal circulation can be sustained by this critical peptide without causing hypotension or compromising glomerular hemodynamics. We have fused our shorter human ACE2 variant with an Albumin binding domain (ABD), as a strategy to extend the duration of action from hours to days. We plan to examine if in mice with syngeneic kidney transplantation administration of this novel ACE2 variant to the recipient that has received a graft subjected to 4 hours of cold ischemia will improve delayed graft function and increase kidney ACE2 activity. Additionally, it will be examined if perfusion of the kidney graft ex vivo with this ACE2 variant prior to kidney transplantation protects against delayed graft function.