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Ram Prasad, Yaqian Duan, Gopalkrishna Sreejit, Jason L. Floyd, Baskaran Athmanathan, Prabhakara R Nagareddy, Maria B Grant; Gut microbiota intensifies retinal vascular defects by targeting adherens junction protein p120-catenin in angiotensin converting enzyme 2 (ACE2) deficient type 1 diabetes (T1D). Invest. Ophthalmol. Vis. Sci. 2019;60(9):977. doi: https://doi.org/.
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Previously, we showed that diabetic retinopathy (DR) was accelerated in a T1D model that had loss of angiotensin converting enzyme 2 (ACE2-/-Akita), a component of the protective arm of the renin angiotensin system. In this study, we sought to determine whether the gut microbiome which is typically altered in T1D may contribute to the deleterious retinal effect we observed in the ACE2-/-Akita mice by increasing microbial products in the circulation.
Wild type (WT), Akita and ACE2-/-Akita mice were studied at 9 months of diabetes. Microbial load in the circulation was assessed by measuring circulating peptidoglycan (PGN) levels along with markers of the gut vascular barrier (GVB). The effect of PGN, a known Toll-like receptor (TLR)-2 agonist, on retinal endothelial cells (HREC) was studied. We specifically focused on PGNs ability to cause retinal damage via activation of the Nlrp3 inflammasome- IL-1b and MyD88/ARNO/ARF6 pathway.
Loss of ACE2 promoted gut barrier permeability through decreased p120-catenin and VE-Cadherin expression in the intestine of ACE2-/-Akita mice. Increased vascular permeability was associated with barrier dysfunction and microbial translocation. The level of plasma PGN (2.5 folds, p<0.007) and acellular capillaries (2 fold, p<0.05) were significantly higher in ACE2-/-Akita mice compared with Akita and wildtype mice. HRECs when treated with PGN showed dissociation of VE-cadherin junctional complexes by depleting p120-catenin. This was mediated through MyD88/ARNO/ARF6 pathway. PGN, a potent signal 1, and in combination with a signal 2 (nigericin) failed to evoke IL-1b release in HRECs.
These data suggest that microbiota-derived PGN has direct deleterious effect on retinal endothelial cells to promote permeability and vascular damage. Strategies aimed at resorting gut health may serve to prevent development of DR.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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