# ACE2 Modulates the Bone Marrow- Gut Axis in Diabetic Retinopathy

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $403,279

## Abstract

This proposal examines the hypothesis that diabetes results in a pathological change in the
communication between the bone marrow (BM) and gut leading to dysfunction in both
compartments. Angiotensin converting enzyme 2 (ACE2) converts angiotensin II (ANG II) to
angiotensin 1-7(Ang 1-7) which, by virtue of its actions on the Mas receptor, opposes the
molecular and cellular effects of ANG II. In human subjects with diabetes, sustained activation
of the ACE2/Ang 1-7/Mas axis in a key BM population (CD34+ cells) was associated with
protection from development of diabetic retinopathy. Ace2/Ace1 mRNA ratio was reduced in
small intestine epithelial cells (IEC) and in BM cells of diabetic mice and these changes are
associated with both gut and BM pathology. Microbiota studies comparing Akita mice and Ace2-
/- Akita mice demonstrate that the loss of ACE2 results in significant phylogenetic differences
and these changes are associated with increased infiltration of proinflammatory BM cells into
the gut.
 These novel findings have led us to propose the following hypothesis: Dysregulated RAS
resulting in reduced ACE2 in BM and gut drives the disturbed BM-gut axis in diabetes.
Increasing ACE2 expression in BM or IEC, either by genetic or pharmacological
manipulations, will restore reciprocal communication between BM and gut preventing
development of diabetic retinopathy.
 Aim 1: In Akita mice, to determine whether increasing ACE2 expression in hematopoietic
cells will facilitate maintenance of endothelial and epithelial barrier functions in retina and gut.
Hematopoietic-specific Ace2 transgenic mice (Vav1-CreAce2KI) will be crossed with Akita mice
to generate Vav1-CreAce2KI.Akita mice (Model 1). Vav1-CreAce2KI will provide donor BM for
BM transplantation into Akita mice (Model 2).
 Aim 2: To determine whether sustained ACE2 expression in hematopoietic cells will prevent
diabetes-induced dysbiosis and development of DR.
 Aim 3. To determine whether correction of dysbiosis by exogenous administration of
genetically modified probiotics expressing ACE2 or overexpression of ACE2 in intestinal
epithelial cells of the gut will protect from development of DR.

## Key facts

- **NIH application ID:** 9932359
- **Project number:** 5R01EY028858-03
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Michael Edwin Boulton
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $403,279
- **Award type:** 5
- **Project period:** 2018-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932359

## Citation

> US National Institutes of Health, RePORTER application 9932359, ACE2 Modulates the Bone Marrow- Gut Axis in Diabetic Retinopathy (5R01EY028858-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9932359. Licensed CC0.

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