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Islam N. Mohamed, Sherif Hafez, Mohammed Abdelsaid, Suraporn Matragoon, Bindu Pillai, Adviye Ergul, John D. Imig, Azza B. El-Remessy; HFD-induced Retinal Microvascular Degeneration: Suggested Role Of Thioredoxin Interacting Protein (TXNIP). Invest. Ophthalmol. Vis. Sci. 2012;53(14):5766. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Obesity and metabolic syndrome are characterized by higher incidence of retinal microvascular abnormalities that coincide with increased oxidative stress and inflammation in non diabetic individuals. However, the molecular events triggering these effects on retinal microvasculature remain elusive. Accumulated evidence supports a key role of thioredoxin-interacting protein (TXNIP) as a metabolic homeostatic switch capable of triggering cellular oxidative, inflammatory and apoptotic response. Our goal was to examine the effect of high fat diet (HFD)-induced obesity on TXNIP expression and development of retinal microvascular lesions in vivo.
8-13 week old male Wistar control rats fed with normal rat chow were compared to rats fed with high fat diet (HFD) (36-45% fat) for 8-10 weeks. Acellular capillary formation was assessed by Periodic acid-Schiff staining. Expression of TXNIP, NFΚB, TNF-α, pro-IL-1β and activation of JNK were assessed by Western Blot.
HFD-induced obesity resulted in significant increases in TXNIP expression (2-fold), activation of proapoptotic stress protein JNK (1.3-fold) and development of retinal acellular capillaries (2-fold), compared to control group. These effects were accompanied by significant increases in retinal oxidative/nitrative stress as indicated by retinal lipid peroxides and nitrotyrosine levels, (1.7 and 1.3 fold), respectively. Total and activated NFΚB expression was higher by (3 and 2.2 fold), that was paralleled with upregulation of downstream pro-inflammatory cytokines TNF-α and pro-IL-1β by (3.3 and 7.2 fold), respectively, relative to control group.
HFD-induced obesity greatly enhances retinal microvascular degeneration. TXNIP upregulation can potentially promote retinal oxidative and inflammatory stress which leads to activation of proapoptotic stress pathways, exacerbation of vascular death, and development of retinopathy. Our findings suggest TXNIP as a novel and potential molecular link between retinal microvascular dysfunction and obesity even before reaching hyperglycemic state. Further characterization of the role of TXNIP in mediating retinal microvascular injury will help to identify novel therapeutic targets for earlier intervention in prediabetic patients.
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