Abstract
Mitochondrial dysfunction is considered to play an important role in the development of diabetic retinopathy. Recent evidence has also shown many similarities between diabetic retinopathy and a low grade chronic inflammatory disease. The aim of this study is to understand the interrelationship between proinflammtory mediator, IL-1β and mitochondrial dysfunction in the accelerated loss of capillary cells in the retina. Using IL-1β receptor gene knockout (IL-1R1−/−) diabetic mice, we have investigated the effect of regulation of IL-1β on mitochondrial dysfunction and mtDNA damage, and increased retinal capillary cell apoptosis and the development of retinopathy. Retinal mitochondrial dysfunction and mtDNA damage were significantly ameliorated in IL-1R1−/− mice, diabetic for ~10 months, compared to the wild-type diabetic mice. This was accompanied by protection of accelerated capillary cell apoptosis and the development of acellular capillaries, histopathology associated with diabetic retinopathy. Thus, mitochondrial damage could be one of the key events via which increased inflammation contributes to the activation of the apoptotic machinery resulting in the development of diabetic retinopathy, and the possible mechanism via which inflammation contributes to the development of diabetic retinopathy includes continuous fueling of the vicious cycle of mitochondrial damage, which could be disrupted by inhibitors of inflammatory mediators.
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References
Kowluru RA. Diabetic retinopathy: mitochondrial dysfunction and retinal capillary cell death. Antioxid Redox Signal. 2005;7:1581–7.
Frank RN. Diabetic retinopathy. N Engl J Med. 2004;350:48–58.
Yuuki T, Kanda T, Kimura Y, Kotajima N, Tamura J, Kobayashi I, et al. Inflammatory cytokines in vitreous fluid and serum of patients with diabetic vitreoretinopathy. J Diabetes Complications. 2001;15:257–9.
Kowluru RA, Odenbach S. Role of interleukin-1beta in the pathogenesis of diabetic retinopathy. British J Ophthalmol. 2004;88:1343–7.
Demircan N, Safran BG, Soylu M, Ozcan AA, Sizmaz S. Determination of vitreous interleukin-1 (IL-1) and tumour necrosis factor (TNF) levels in proliferative diabetic retinopathy. Eye. 2006;20:1366–9.
Krady JK, Basu A, Allen CM, Xu Y, LaNoue KF, Gardner TW, et al. Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy. Diabetes. 2005;54:1559–65.
Kern TS. Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy. Exp Diabetes Res. 2007;2007:95103.
Felinski EA, Antonetti DA. Glucocorticoid regulation of endothelial cell tight junction gene expression: novel treatments for diabetic retinopathy. Curr Eye Res. 2005;30:949–57.
Kowluru RA, Kanwar M. Effect of curcumin on retinal oxidative stress and inflammation in diabetes. Nutr Metab (Lond). 2007;4:1–8.
Tang J, Kern TS. Inflammation in diabetic retinopathy. Prog Retin Eye Res. 2011;30:343–58.
Madsen-Bouterse SA, Mohammad G, Kanwar M, Kowluru RA. Role of mitochondrial DNA damage in the development of diabetic retinopathy, and the metabolic memory phenomenon associated with its progression. Antioxid Redox Signal. 2010;13:797–805.
Madsen-Bouterse S, Zhong Q, Mohammad G, Ho YS, Kowluru RA. Oxidative damage of mitochondrial DNA in diabetes, and its protection by manganese superoxide dismutase. Free Rad Res. 2010;44:313–21.
Kowluru RA, Abbas SN. Diabetes-induced mitochondrial dysfunction in the retina. Inves Ophthalmol Vis Sci. 2003;44:5327–34.
Kowluru RA, Tang J, Kern TS. Abnormalities of retinal metabolism in diabetes and experimental galactosemia. VII. Effect of long-term administration of antioxidants on the development of retinopathy. Diabetes. 2001;50:1938–42.
Kowluru RA, Odenbach S. Role of interleukin-1beta in the development of retinopathy in rats: effect of antioxidants. Invest Ophthalmol Vis Sci. 2004;45:4161–6.
Hallegua DS, Weisman MH. Potential therapeutic uses of interleukin 1 receptor antagonists in human diseases. Ann Rheum Dis. 2002;61:960–7.
Vincent JA, Mohr S. Inhibition of caspase-1/interleukin-1beta signaling prevents degeneration of retinal capillaries in diabetes and galactosemia. Diabetes. 2007;56:224–30.
Kowluru RA, Kowluru V, Ho YS, Xiong Y. Overexpression of mitochondrial superoxide dismutase in mice protects the retina from diabetes-induced oxidative stress. Free Rad Biol Med. 2006;41:1191–6.
Mohammad G, Kowluru RA. Matrix metalloproteinase-2 in the development of diabetic retinopathy and mitochondrial dysfunction. Lab Invest. 2010;90:1365–72.
Kowluru RA, Mohammad G, Santos JM, Zhong Q. Abrogation of MMP9 gene protects against the development of retinopathy in diabetic mice by preventing mitochondrial damage. Diabetes 2011;60:3023–33.
Zhong Q, Kowluru RA. Epigenetic changes in mitochondrial superoxide dismutase in the retina and the development of diabetic retinopathy. Diabetes. 2011;60:1304–13.
Santos JM, Tewari S, Goldberg AFX, Kowluru RA. Mitochondria biogenesis and the development of diabetic retinopathy. Free Rad Biol Med 2011;51:1849–60.
Mohammad G, Kowluru RA. Novel role of mitochondrial matrix metalloproteinase-2 in the development of diabetic retinopathy. Invest Ophthalmol Vis Sci. 2011;52:3832–41.
Kanwar M, Chan PS, Kern TS, Kowluru RA. Oxidative damage in the retinal mitochondria of diabetic mice: possible protection by superoxide dismutase. Invest Ophthalmol Vis Sci. 2007;48:3805–11.
Kern TS, Tang J, Mizutani M, Kowluru R, Nagraj R, Lorenzi M. Response of capillary cell death to aminoguanidine predicts the development of retinopathy: comparison of diabetes and galactosemia. Invest Ophthalmol Vis Sci. 2000;41:3972–8.
Hunter RL, Dragicevic N, Seifert K, Choi DY, Liu M, Kim HC, et al. Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system. J Neurochem. 2007;100:1375–86.
Yoneda S, Tanihara H, Kido N, Honda Y, Goto W, Hara H, et al. Interleukin-1beta mediates ischemic injury in the rat retina. Exp Eye Res. 2001;73:661–7.
Zheng L, Gong B, Hatala DA, Kern TS. Retinal ischemia and reperfusion causes capillary degeneration: similarities to diabetes. Invest Ophthalmol Vis Sci. 2007;48:361–7.
Busik JV, Mohr S, Grant MB. Hyperglycemia-induced reactive oxygen species toxicity to endothelial cells is dependent on paracrine mediators. Diabetes. 2008;57:1952–65.
Tschopp J. Mitochondria: sovereign of inflammation? Eur J Immunol. 2011;41:1196–202.
Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469:221–5.
Green DR, Galluzzi L, Kroemer G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science. 2011;333:1109–12.
Acknowledgments
The authors thank Yakov Shamailov and Dug Putt for their help in maintaining the mouse colony. This work was supported, in part, by grants from the National Institutes of Health, Juvenile Diabetes Research Foundation, The Thomas Foundation and Research to Prevent Blindness.
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Kowluru, R.A., Mohammad, G., Santos, J.M. et al. Interleukin-1β and mitochondria damage, and the development of diabetic retinopathy. j ocul biol dis inform 4, 3–9 (2011). https://doi.org/10.1007/s12177-011-9074-6
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DOI: https://doi.org/10.1007/s12177-011-9074-6