Book excerpt: Angiotensin-converting enzyme 2 (ACE2) is the primary enzyme of the vasoprotective axis of the renin-angiotensin system (RAS). We tested the hypothesis that the protective arm of the RAS axis can i) act to maintain homeostasis in the diabetic bone marrow stem cell compartment, ii) regulate the reparative function of the hematopoietic stem/progenitor cells (HSPCs) and iii) modulate the gut microbiota composition. All processes could influence the development of diabetic retinopathy. Diabetic ACE2 knockout (KO)/C57BL/6-Ins2WT/C96Y (Akita) mice were examined at 3 and 9 months after the onset of diabetes and compared to age-matched controls. Both ACE2KO-Akita and Akita cohorts showed reduced retinal thickness by optical coherence tomography at 9 months of diabetes. The absence of ACE2 in 9-month diabetic mice led to an accelerated increase in acellular capillaries, a hallmark feature of diabetic retinopathy. The absence of ACE2 also caused a reduction of both long-term and short-term repopulating HSPCs in the diabetic bone marrow at 9 months of diabetes. Reparative function studies showed that ACE2KO exacerbated diabetes-induced impairment of lineage-c-kit+ HSPC migration and proliferation as early as 3-month of diabetes. HSPCs from both early and late stage diabetic mice, pretreated with Ang-(1-7) or alamandine (two downstream peptides of ACE2) showed restored migration and proliferation. The gut microbiota has been implicated in the pathogenesis of diabetes. Analysis of the gut microbiome also revealed a distinct bacterial profile in ACE2KO-Akita group, with a great diversity of bacterial types that were previously reported to contribute to diabetic pathogenesis, including Tenericutes at the phylum level and Mollicutes at the class level, and with an activation of peptidoglycan biosynthesis pathways. Flow cytometry analysis showed that loss of ACE2 led to less infiltration of circulating angiogenic cells in the gut which may lead to an increased endothelial cell permeability in the intestinal endothelium. This leakage into the blood may promote systemic inflammation known to contribute to the pathogenesis of diabetic retinopathy. These data suggested a loss of the protective arm of RAS contributes to the impairment of HSPCs and alteration of gut microbiota, both of which may contribute to the development of diabetic retinopathy.