Document text
Principal Investigator: DANIEL BATLLE
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2022
Award: $320,000
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <ACE2><Acute><Acute Kidney Failure><Acute Kidney Insufficiency><Acute Renal Failure><Acute Renal Failure with Renal Papillary Necrosis><Acute Renal Insufficiency><Adrenergic alpha-Antagonists><Adrenergic alpha-Blockers><Adrenergic alpha-Receptor Blockaders><Adrenergic α-Antagonists><Adrenergic α-Blockers><Affect><Albumins><Allogenic><Amino Acids><AngII><Angiotensin II><Angiotensins><Attenuated><Binding><Biomedical Engineering><Body Tissues><Cessation of life><Chimera Protein><Chimeric Proteins><Clinical><Data><Death><Dialysis><Dialysis procedure><Enzyme Gene><Enzymes><FDA approved><Fostering><Fusion Protein><Genetic Models><Goals><Health Expenditures><Hour><Human><Hypotension><Infusion><Infusion procedures><Injury><Ischemia><Ischemia-Reperfusion Injury><Kidney><Kidney Circulation><Kidney Grafting><Kidney Transplantation><Kidney Transplants><Kidney Urinary System><L-Lysine><Low Blood Pressure><Lysine><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Murine><Mus><Organ><Patients><Peptides><Perfusion><Phenylalanine><Prevention><Production><Property><Proteins><Proximal Kidney Tubules><Renal Circulation><Renal Grafting><Renal Transplantation><Renal Transplants><Reperfusion Damage><Reperfusion Injury><Reperfusion Therapy><Reporting><Testing><Therapeutic Effect><Tissues><Transplant Recipients><Tubular><Tubular formation><Urine><Urine Urinary System><Variant><Variation><Vascular Hypotensive Disorder><acute kidney injury><allograft rejection><alpha adrenergic blockade><alpha antiadrenergic agent><alpha blocker><alpha-Adrenergic Blocking Agents><aminoacid><angiotensin converting enzyme 2><angiotensin converting enzyme II><bio-engineered><bio-engineers><bioengineering><biological engineering><delayed graft function><dialysis therapy><driving force><glomerular filtration><health care expenditure><healthcare expenditure><hemodynamics><high risk><improved><injuries><kidney tx><molecular size><mouse model><murine model><new approaches><novel><novel approaches><novel strategies><novel strategy><prevent><preventing><protective effect><renal><renal proximal tubule><reperfusion><tool><transplant patient><α blocker>