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Islam N Mohamed, Sally Lotfy Elshaer, Megan Clendenning, Azza B El-Remessy; TXNIP deletion abrogates high fat diet-induced retinal inflammation and microvascular injury. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4918.
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Obesity and prediabetes affect ~79 Million Americans, however little is known whether these conditions cause retinal injury before incidence of diabetes. Our group has shown that high fat diet (HFD) induces retinal NOD-like receptor protein (NLRP3)-inflammasome activation and leukostasis in wild type mice and rats and that thioredoxin interacting protein (TXNIP) is required for NLRP3 inflammasome activation in retinal endothelial cells. Therefore, we hypothesized that TXNIP deletion can protect against HFD-induced retinal inflammation, blood retinal barrier (BRB) breakdown and microvascular degeneration.
6-weeks old age and gender matched C57Bl/6J wild type mice and TXNIP knock out mice fed with normal chow (WT-ND and TKO-ND) were compared to their littermates fed with HFD (60% fat) (WT-HFD and TKO-HFD) for 8 or 18-weeks. Human retinal endothelial cells (HRECs) were incubated with 400µM sodium palmitate coupled to bovine serum albumin (Pal-BSA) for 12-hours. Breakdown of blood retina barrier was assessed by extravasation of BSA-fluorescien. Acellular capillary was detected using PASH staining.
HFD resulted in obesity evident by significant increases in total body weight in both WT and TKO mice, however, TKO mice were protected against HFD-induced insulin resistance. In comparison to WT-ND, there was significant increases in retinal NLRP3 inflammasome activation evidenced by increased NLRP3, cleaved caspase-1 and cleaved IL-1β by 1.6, 2.3 and 2.7-fold, respectively in WT-HFD but not in TKO-HFD mice. These effects coincided with increased retinal leukostasis and microvascular permeability by 1.4 and ~3-fold, respectively, at 8-weeks and development of acellular capillary formation by 1.5-fold in WT-HFD but not in TKO-HFD mice after 18-weeks. In-vitro, knocking down TXNIP inhibited Pal-BSA induction of adhesion molecules; ICAM-1 and PECAM-1 in HRECs and protected against Pal-BSA-induced IL-1β expression and cell death.
These studies support a role of obesity and prediabetes in the development of retinal inflammation and early vascular lesions before incidence of frank diabetes. Our findings establish TXNIP as a protein that couples HFD-induced microvascular inflammation to early microvascular injury via NLRP3-inflammasome activation. Delineating this mechanism identifies TXNIP as a novel therapeutic target for early intervention in obesity and prediabetic retinopathy.
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