Abstract
Purpose :
Previously, we showed that the loss of angiotensin converting enzyme 2 (ACE2) results in disturbed gut-retina axis and contributes to developing diabetic retinopathy (DR). However, the mechanisms responsible for causing DR phenotype are poorly understood. Here, we examined the impact of maintained levels of enteral ACE2 on gut barrier defects, glucose homeostasis, and the development of DR in type 1 diabetic (T1D) mice.
Methods :
Two approaches were employed to maintain enteral ACE2 levels in the Akita mice. 1) overexpression of human Ace2 in Akita mice (Vil-Cre.Ace2KI-Akita) by genetic manipulation, and 2) oral administration of an engineered probiotic (Lactobacillus paracasei; LP) which expressed and secreted humanized ACE2 into the intestinal lumen. After nine months of T1D, enteral and retinal endpoints were assessed, including expression of local RAS components, gut barrier integrity, visual function, and histological features of DR.
Results :
Despite the presence of nine months of diabetes, Vil-Cre.Ace2KI-Akita and LP-ACE2-Akita mice exhibit sustained intestinal Ang 1-7 levels, preserved junctional proteins (ZO-1, p120-catenin, β-catenin), and maintained gut barrier integrity as demonstrated by lower levels of gut microbial products in the systemic circulation. Increased ACE2 activity leads to Ang-II degradation, resulting in higher Ang1-7 levels. Ang1-7, through activation of the Mas receptor, increases intestinal glucose transporters (SGLT1 and GLUT2). Furthermore, enteral ACE2 forms a heterodimer with the tryptophan transporter B0AT1, as observed by IHC, which increased incretin (GLP-1 and GIP) secretion. These act in combination to control glucose homeostasis, which, within the retina, reduced acellular capillaries in Vil-Cre.Ace2KI-Akita (p<0.001) and LP-ACE2 treated Akita mice (p<0.0001) compared with untreated diabetic mice. Sustained enteral ACE2 expression also significantly improved retinal electrical response and visual acuity as measured by ERG (scotopic a wave, p<0.003; scotopic b wave, p<0.01; photopic a wave, ns; photopic b wave, p<0.002) and OKN (p<0.0001), respectively.
Conclusions :
Taken together, our study demonstrates that sustained enteral ACE2 expression in T1D prevents DR by maintaining intestinal barrier integrity and improving glucose homeostasis.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.