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Mutual enhancement between high-mobility group box-1 and NADPH oxidase-derived reactive oxygen species mediates diabetes-induced upregulation of retinal apoptotic markers

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Abstract

The expression of the proinflammatory cytokine high-mobility group box-1 (HMGB1) is upregulated in epiretinal membranes and vitreous fluid from patients with proliferative diabetic retinopathy (PDR) and in the diabetic retina. We hypothesized that a novel mechanism exists where HMGB1 and NADPH oxidase (Nox)-derived reactive oxygen species (ROS) are mutually enhanced in the diabetic retina, which may be a novel mechanism for promoting upregulation of retinal apoptotic markers induced by diabetes. Vitreous samples from 48 PDR and 34 nondiabetic patients, retinas from 1-month diabetic rats and from normal rats intravitreally injected with HMGB1 and human retinal microvascular endothelial cells (HRMEC) stimulated with HMGB1 were studied by enzyme-linked immunosorbent and spectrophotometric assays, Western blot analysis, RT-PCR, and immunofluorescence. We also studied the effect of the HMGB1 inhibitor glycyrrhizin and apocynin on diabetes-induced biochemical changes in the retinas of rats (n = 5–7 in each groups). HMGB1 and the oxidative stress marker protein carbonyl content levels in the vitreous fluid from PDR patients were significantly higher than in controls (p = 0.021; p = 0.005, respectively). There was a significant positive correlation between vitreous fluid levels of HMGB1 and the levels of protein carbonyl content (r = 0.62, p = 0.001). HMGB1 enhanced interleukin-1β, ROS, Nox2, poly (ADP-ribose) polymerase (PARP)-1, and cleaved caspase-3 production by HRMEC. Diabetes and intravitreal injection of HMGB1 in normal rats induced significant upregulation of ROS, Nox2, PARP-1, and cleaved caspase-3 in the retina. Constant glycyrrhizin and apocynin intake from onset of diabetes did not affect the metabolic status of the diabetic rats, but restored these increased mediators to control values. The results of this study suggest that there is a mutual enhancement between HMGB1 and Nox-derived ROS in the diabetic retina, which may promote diabetes-induced upregulation of retinal apoptotic markers.

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Acknowledgments

The authors thank Ms. Connie B. Unisa-Marfil for secretarial work. This project was funded by National Plan for Science, Technology and Innovation (MAARIFAH), King Abdulaziz City for Science and Technology, Kingdom of Saudi Arabia, Award number (12-MED2604-02) and Dr. Nasser Al-Rashid Research Chair in Ophthalmology (Abu El-Asrar AM).

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Authors and Affiliations

  1. Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia

    Ghulam Mohammad, Kaiser Alam, Mohammad Imtiaz Nawaz, Mohammad Mairaj Siddiquei, Ahmed Mousa & Ahmed M. Abu El-Asrar

  2. Dr. Nasser Al-Rashid Research Chair in Ophthalmology, Riyadh, Saudi Arabia

    Ghulam Mohammad, Kaiser Alam, Mohammad Imtiaz Nawaz, Mohammad Mairaj Siddiquei & Ahmed M. Abu El-Asrar

  3. Department of Ophthalmology, King Abdulaziz University Hospital, Old Airport Road, P.O. Box 245, Riyadh, 11411, Saudi Arabia

    Ghulam Mohammad

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  1. Ghulam Mohammad
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Mohammad, G., Alam, K., Nawaz, M.I. et al. Mutual enhancement between high-mobility group box-1 and NADPH oxidase-derived reactive oxygen species mediates diabetes-induced upregulation of retinal apoptotic markers. J Physiol Biochem 71, 359–372 (2015). https://doi.org/10.1007/s13105-015-0416-x

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