Delayed graft function (DGF) is a form of acute renal failure and is 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 used, even though these kidneys are at higher risk to develop DGF. DGF is primarily caused by acute tubular necrosis induced by ischemia and reperfusion injury. Ischemic injury and reperfusion injury are complex processes and begin already pre-transplantation. Patients with DGF have a higher risk of allograft rejection and death. Recipient factors associated with higher risk for death with DGF include older age, diabetes or hypertension as the cause of end-stage renal disease (ESRD) and longer duration of dialysis prior to transplantation. DGF also leads to increased health expenditures. There are no FDA-approved treatments available to date. Treatment or prevention of delayed graft function, therefore, poses an unmet clinical need. Approaches to prevent and attenuate DGF are urgently needed. In this proposal, we want to examine the preventative value of a shorter angiotensin converting enzyme (ACE2) variant that we have evidence that in mice it protects against acute kidney injury (AKI) caused by ischemia reperfusion injury (IRI). As ischemia reperfusion injury is the driving force of DGF, we propose to use our ACE2 variant to 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. Moreover, a decrease in ACE2 activity and Ang (1-7) has been reported by us in AKI and others. We propose to prevent and attenuate DGF by providing our short ACE2 variant with extended duration of action (ACE2-ABD) that can be filtered and taken up by the kidney where it fosters the degradation of Ang II and thus production 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. Enhancing the degradation of Ang II by increasing ACE2 activity offers a more natural approach to deal with Ang II excess in AKI than using RAS blockers, which either prevent Ang II formation or block its receptors. ACE2 is a tissue enzyme that has been reported decreased in kidneys from mice with AKI and in mice with genetic ACE2 deficiency, kidney injury induced by ischemia-reperfusion is exacerbated. Ang (1-7), a peptide that may normally exert a reno-protective action, has been reported decreased in the ischemia-reperfusion model of AKI.
|Effective start/end date||11/1/21 → 10/31/23|
- National Institute of Allergy and Infectious Diseases (5R21AI166940-02)
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