Loss of Angiotensin-Converting Enzyme 2 Exacerbates Diabetic Retinopathy by Promoting Bone Marrow Dysfunction

Abstract

Angiotensin-converting enzyme 2 (ACE2) is the primary enzyme of the vasoprotective axis of the renin angiotensin system (RAS). We tested the hypothesis that loss of ACE2 would exacerbate diabetic retinopathy by promoting bone marrow dysfunction. ACE2 were crossed with Akita mice, a model of type 1 diabetes. When comparing the bone marrow of the ACE2 -Akita mice to that of Akita mice, we observed a reduction of both short-term and long-term repopulating hematopoietic stem cells, a shift of hematopoiesis toward myelopoiesis, and an impairment of lineage c-kit hematopoietic stem/progenitor cell (HS/PC) migration and proliferation. Migratory and proliferative dysfunction of these cells was corrected by exposure to angiotensin-1-7 (Ang-1-7), the protective peptide generated by ACE2. Over the duration of diabetes examined, ACE2 deficiency led to progressive reduction in electrical responses assessed by electroretinography and to increases in neural infarcts observed by fundus photography. Compared with Akita mice, ACE2 -Akita at 9-months of diabetes showed an increased number of acellular capillaries indicative of more severe diabetic retinopathy. In diabetic and control human subjects, CD34 cells, a key bone marrow HS/PC population, were assessed for changes in mRNA levels for MAS, the receptor for Ang-1-7. Levels were highest in CD34 cells from diabetics without retinopathy. Higher serum Ang-1-7 levels predicted protection from development of retinopathy in diabetics. Treatment with Ang-1-7 or alamandine restored the impaired migration function of CD34 cells from subjects with retinopathy. These data support that activation of the protective RAS within HS/PCs may represents a therapeutic strategy for prevention of diabetic retinopathy. Stem Cells 2018;36:1430-1440.

The Gut–Eye Axis: Lessons Learned from Murine Models

“…Probiotics have been shown to improve intestinal health via inhibition of pathogenic species colonization, improvement of gut barrier function, and modulation of gut immunity [99]. As mentioned previously, diabetic mice exhibit decreased intestinal levels of ACE2 [13,51]. It is hypothesized that probiotic replenishment of ACE2 via oral administration of live bacteria which produce ACE2 will improve gut barrier function, restructure the gut microbiota to homeostatic levels, and prevent pathological translocation of PGN into the circulation [100].…”

“…Dysfunction of the renin-angiotensin system (RAS) is associated with diabetes and vascular dysfunction, particularly diabetic retinopathy [43][44][45][46][47][48][49][50][51]. This effect is largely mediated by the loss of angiotensin-converting enzyme 2 (ACE2), the primary protein responsible for shifting the effects of RAS between its vasoprotective and vasodeleterious arms by its action on the MAS receptor and ATR1/ATR2, respectively [52][53][54].…”

“…It is hypothesized that probiotic replenishment of ACE2 via oral administration of live bacteria which produce ACE2 will improve gut barrier function, restructure the gut microbiota to homeostatic levels, and prevent pathological translocation of PGN into the circulation [100]. Together, this treatment has the potential to reduce DR pathology, as these have all been shown to play a role in the progression of DR in mouse models of type 1 and type 2 diabetes [13,51]. Pre-and probiotic interventions show promise in that they are a less invasive therapeutic option with minimal risk for complications.…”

Targeting Angiotensin-Converting Enzyme-2/Angiotensin-(1-7)/Mas Receptor Axis in the Vascular Progenitor Cells for Cardiovascular Diseases

“…Importantly, mobilization of progenitors into the circulation in response to ischemic vascular injury is severely impaired resulting in partial recovery of blood flow to the ischemic areas (Vasam et al, 2017). Mice with ACE2 deficiency were shown to develop bone marrow dysfunction characterized by skewing hematopoiesis towards myelopoiesis, which increased the susceptibility to the development of microvascular complications (Duan et al, 2018). This observation is indeed in agreement with findings from studies by using Ang II (Jun et al, 2012;Kim et al, 2016), suggesting that the absence of the counter-regulatory vasoprotective axis produces detrimental effects in the bone marrow largely via ACE/Ang II/AT1R overactivity.…”

Effect of angiotensin II and angiotensin‐(1–7) on proliferation of stem cells from human dental apical papilla

“…Ang‐(1–7) alone or in combination with colony‐stimulating factors increased myeloid, megakaryocytic, and erythroid progenitor cells, suggesting a pluripotent multilineage stimulatory activity (Rodgers et al, 2012, 2013). Ang‐(1–7) also induced proliferation of CD34 + (Singh et al, 2015) and c‐Kit + (Duan et al, 2018) cells.…”