Dataset Information

Maintenance of Enteral ACE2 Prevents Diabetic Retinopathy in Type 1 Diabetes.

ABSTRACT:

Background

We examined components of systemic and intestinal renin-angiotensin system on gut barrier permeability, glucose homeostasis, systemic inflammation, and progression of diabetic retinopathy (DR) in human subjects and mice with type 1 diabetes (T1D).

Methods

T1D individual with (n=18) and without (n=20) DR and controls (n=34) were examined for changes in gut-regulated components of the immune system, gut leakage markers (FABP2 [fatty acid binding protein 2] and peptidoglycan), and Ang II (angiotensin II); Akita mice were orally administered a Lactobacillus paracasei (LP) probiotic expressing humanized ACE2 (angiotensin-converting enzyme 2) protein (LP-ACE2) as either a prevention or an intervention. Akita mice with genetic overexpression of humanAce2 by small intestine epithelial cells (Vil-Cre.hAce2KI-Akita) were similarly examined. After 9 months of T1D, circulatory, enteral, and ocular end points were assessed.

Results

T1D subjects exhibit elevations in gut-derived circulating immune cells (ILC1 cells) and higher gut leakage markers, which were positively correlated with plasma Ang II and DR severity. The LP-ACE2 prevention cohort and genetic overexpression of intestinal ACE2 preserved barrier integrity, reduced inflammatory response, improved hyperglycemia, and delayed development of DR. Improvements in glucose homeostasis were due to intestinal MasR activation, resulting in a GSK-3β (glycogen synthase kinase-3 beta)/c-Myc (cellular myelocytomatosis oncogene)-mediated decrease in intestinal glucose transporter expression. In the LP-ACE2 intervention cohort, gut barrier integrity was improved and DR reversed, but no improvement in hyperglycemia was observed. These data support that the beneficial effects of LP-ACE2 on DR are due to the action of ACE2, not improved glucose homeostasis.

Conclusions

Dysregulated systemic and intestinal renin-angiotensin system was associated with worsening gut barrier permeability, gut-derived immune cell activation, systemic inflammation, and progression of DR in human subjects. In Akita mice, maintaining intestinal ACE2 expression prevented and reversed DR, emphasizing the multifaceted role of the intestinal renin-angiotensin system in diabetes and DR.

SUBMITTER: Prasad R

PROVIDER: S-EPMC9822874 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Maintenance of Enteral ACE2 Prevents Diabetic Retinopathy in Type 1 Diabetes.

Prasad Ram R Floyd Jason L JL Dupont Mariana M Harbour Angela A Adu-Agyeiwaah Yvonne Y Asare-Bediako Bright B Chakraborty Dibyendu D Kichler Kara K Rohella Aayush A Li Calzi Sergio S Lammendella Regina R Wright Justin J Boulton Michael E ME Oudit Gavin Y GY Raizada Mohan K MK Stevens Bruce R BR Li Qiuhong Q Grant Maria B MB

Circulation research 20221130 1

<h4>Background</h4>We examined components of systemic and intestinal renin-angiotensin system on gut barrier permeability, glucose homeostasis, systemic inflammation, and progression of diabetic retinopathy (DR) in human subjects and mice with type 1 diabetes (T1D).<h4>Methods</h4>T1D individual with (n=18) and without (n=20) DR and controls (n=34) were examined for changes in gut-regulated components of the immune system, gut leakage markers (FABP2 [fatty acid binding protein 2] and peptidoglyc ...[more]

PMID: 36448480

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Project description:BackgroundThe proportion of patients with diabetic retinopathy (DR) has grown with increasing number of diabetes mellitus patients in the world. It is among the major causes of blindness worldwide. The main objective of this study was to identify contributing risk factors of DR among people with type II diabetes mellitus.MethodA sample of 191 people with type II diabetes mellitus was selected from the Black Lion Specialized Hospital diabetic unit from 1 March 2018 to 1 April 2018. A multivariate stochastic regression imputation technique was applied to impute the missing values. The response variable, DR is a categorical variable with two outcomes. Based on the relationship derived from the exploratory analysis, the odds of having DR were not necessarily linearly related to the continuous predictors for this sample of patients. Therefore, a semiparametric model was proposed to identify the risk factors of DR.ResultFrom the sample of 191 people with type II diabetes mellitus, 98 (51.3%) of them had DR. The results of semiparametric regression model revealed that being male, hypertension, insulin treatment, and frequency of clinical visits had a significant linear relationships with the odds of having DR. In addition, the log- odds of having DR has a significant nonlinear relation with the interaction of age by gender (for female patients), duration of diabetes, interaction of cholesterol level by gender (for female patients), haemoglobin A1c, and interaction of haemoglobin A1c by fasting blood glucose with degrees of freedom [Formula: see text], respectively. The interaction of age by gender and cholesterol level by gender appear non significant for male patients. The result from the interaction of haemoglobin A1c (HbA1c) by fasting blood glucose (FBG) showed that the risk of DR is high when the level of HbA1c and FBG were simultaneously high.ConclusionClinical variables related to people with type II diabetes mellitus were strong predictive factors of DR. Hence, health professionals should be cautious about the possible nonlinear effects of clinical variables, interaction of clinical variables, and interaction of clinical variables with sociodemographic variables on the log odds of having DR. Furthermore, to improve intervention strategies similar studies should be conducted across the country.

Project description:Aims/hypothesisThe loss of pericytes surrounding the retinal vasculature in early diabetic retinopathy underlies changes to the neurovascular unit that lead to more destructive forms of the disease. However, it is unclear which changes lead to loss of retinal pericytes. This study investigated the hypothesis that chronic increases in one or more inflammatory factors mitigate the signalling pathways needed for pericyte survival.MethodsLoss of pericytes and levels of inflammatory markers at the mRNA and protein levels were investigated in two genetic models of diabetes, Ins2Akita/+ (a model of type 1 diabetes) and Leprdb/db (a model of type 2 diabetes), at early stages of diabetic retinopathy. In addition, changes that accompany gliosis and the retinal vasculature were determined. Finally, changes in retinal pericytes chronically incubated with vehicle or increasing amounts of IFNγ were investigated to determine the effects on pericyte survival. The numbers of pericytes, microglia, astrocytes and endothelial cells in retinal flatmounts were determined by immunofluorescence. Protein and mRNA levels of inflammatory factors were determined using multiplex ELISAs and quantitative reverse transcription PCR (qRT-PCR). The effects of IFNγ on the murine retinal pericyte survival-related platelet-derived growth factor receptor β (PDGFRβ) signalling pathway were investigated by western blot analysis. Finally, the levels of cell death-associated protein kinase C isoform delta (PKCδ) and cleaved caspase 3 (CC3) in pericytes were determined by western blot analysis and immunocytochemistry.ResultsThe essential findings of this study were that both type 1 and 2 diabetes were accompanied by a similar progression of retinal pericyte loss, as well as gliosis. However, inflammatory factor expression was dissimilar in the two models of diabetes, with peak expression occurring at different ages for each model. Retinal vascular changes were more severe in the type 2 diabetes model. Chronic incubation of murine retinal pericytes with IFNγ decreased PDGFRβ signalling and increased the levels of active PKCδ and CC3.Conclusions/interpretationWe conclude that retinal inflammation is involved in and sustains pericyte loss as diabetic retinopathy progresses. Moreover, IFNγ plays a critical role in reducing pericyte survival in the retina by reducing activation of the PDGFRβ signalling pathway and increasing PKCδ levels and pericyte apoptosis.

Dataset Information

Maintenance of Enteral ACE2 Prevents Diabetic Retinopathy in Type 1 Diabetes.

Background

Methods

Results

Conclusions

Publications

Maintenance of Enteral ACE2 Prevents Diabetic Retinopathy in Type 1 Diabetes.

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