# Novel Short ACE2 variant for Delayed Graft Function

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2023 · $120,000

## Abstract

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.

## Key facts

- **NIH application ID:** 10514607
- **Project number:** 5R21AI166940-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** DANIEL BATLLE
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $120,000
- **Award type:** 5
- **Project period:** 2021-11-01 → 2024-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10514607

## Citation

> US National Institutes of Health, RePORTER application 10514607, Novel Short ACE2 variant for Delayed Graft Function (5R21AI166940-02). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10514607. Licensed CC0.

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