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Abstract
Diabetic retinopathy (DR) is a leading cause of blindness in US adults. DR starts with an early vaso-regressive stage of non-proliferative diabetic retinopathy (NPDR), which progresses into proliferative diabetic retinopathy (PDR). Over one-third of U.S. adults are obese. Obesity is now considered a disease state, rather than a mere risk stage for developing metabolic syndrome. Clinical and experimental evidence signifies glycemia, hypertension, and obesity as independent risk factors for developing retinopathy and retinal microvascular abnormalities in non-diabetic populations or on top of type 1 or 2 diabetes. It also emphasizes caspase-1/IL- activation as a major pathophysiological component. However, data from experimental models are lacking and little is known about the upstream molecular mechanisms involved. Therefore, the overall goal of current studies is to model the detrimental effects of obesity and hypertension on instigating early stage retinal microvascular lesions. In the first study, HFD-induced obesity or hypertension showed similar effects on early retinal microvascular lesions, thioredoxin interacting protein (TXNIP) expression, oxidative and inflammatory stress. However, HFD selectively increased TXNIP-NLRP3 (NOD-like receptor protein) interaction, inflammasome activation and cleaved caspase-1 and IL-1 expression. Moreover, retinal vasculature and surrounding macroglial tissue were prominent sites for HFD-induced TXNIP up-regulation. In the second study, TXNIP deletion in TXNIP knockout (TKO) mice mitigated HFD-induced retinal NLRP3 inflammasome activation, adhesion molecule upregulation, leukostasis and blood retinal barrier (BRB) breakdown on the short term, and acellular capillaries formation and microvascular abnormalities on the long term. TXNIP-NLRP3-inflammasome activation in human retinal endothelial (HRE) cells was confirmed in-vitro in response to saturated fatty acid palmitate; a direct activator of the NLRP3-inflammasome. TXNIP was also required for palmitate-induced adhesion molecule upregulation in HRE cells and TXNIP-NLRP3 inflammasome axis mediated the process in an autotocrine positive feedback loop fashion. Furthermore, circulating leukocytes from HFD wild-type (WT) mice and obese subjects resulted in increased leukostasis and endothelial cell death in culture in a TXNIP dependent manner. In summary, our findings highlight the early detrimental effects of HFD-induced obesity on the development of retinal microvascular lesions. TXNIP-NLRP3 inflammasome axis provides novel therapeutic targets for earlier intervention or prevention of obesity and pre-diabetes microvascular complications.