Pharmacologic Induction of Heme Oxygenase-1 Plays a Protective Role in Diabetic Retinopathy in Rats

被引：88
作者：
Fan, Jiawen [1 ]
Xu, Gezhi [1 ,2 ]
Jiang, Tingting [1 ]
Qin, Yaowu [1 ]
机构：
[1] Fudan Univ, Inst Eye, EENT Hosp, Shanghai 200433, Peoples R China
[2] Fudan Univ, Inst Brain Sci, Shanghai 200433, Peoples R China
来源：
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE | 2012年 / 53卷 / 10期
关键词：
ISCHEMIA-REPERFUSION INJURY; OXIDATIVE STRESS; SUPEROXIDE-DISMUTASE; GENE-EXPRESSION; UP-REGULATION; MULLER CELLS; HYPOXIA; OVEREXPRESSION; ANTIOXIDANT; RECEPTOR;
D O I：
10.1167/iovs.11-9241
中图分类号：
R77 [眼科学];
学科分类号：
100212 ;
摘要：
PURPOSE. We investigated the protective effects of HO-1, induced by hemin, in the retinas of streptozotocin (STZ)-induced diabetic rats, and document the possible anti-inflammatory, anti-apoptotic, and anti-proliferative mechanisms underlying the protection. METHODS. Sprague-Dawley (SD) rats were induced to diabetes by intraperitoneal injection of STZ (60 mg/kg). Later, some of the rats were given intraperitoneal injections of hemin (20 mg/kg) to induce expression of HO-1. The protective effects of hemin were evaluated by examining the hemoglobin concentration (Hb) and the glycosylated hemoglobin (HbA1c) level of blood from the rats, further calculating the numbers of TUNEL positive cells in retinal ganglion cell (RGC) layer and diI-labeled RGCs. We also documented the expressions of HO-1, HIF-1 alpha, SOD-1, VEGF, p53, and bcl-2 by Western blot analysis and real-time quantitative PCR. Expressions of Nrf2, tERK 1/2;, and pERK 1/2 were detected only by Western blot analysis. HO-1, Nrf2, pERK, and GFAP proteins were detected by immunofluorescence. RESULTS. The Hb level was higher in hemin-treated rat blood than nontreated diabetic group, while the HbA1c level was lower. Hemin significantly activated HO-1 expression in the retinas of diabetic rats, combined with accordant changes of Nrf2/pERK protein expression, and upregulated the expression of GFAP in retina. Retinal ganglion cells displayed greater sensitivity to apoptosis when the HO-1 level was lower. Overexpression of HO-1 was associated with an increase in the activation of SOD-1 and bcl-2, and a decrease of the expression of HIF-1a, VEGF, and p53. CONCLUSIONS. HO-1 is an important positive modulator of the Nrf2/ERK-related signaling. Overexpression of HO-1 by hemin induction protected retinal ganglion cells in diabetic retinopathy through anti-inflammatory, anti-apoptotic, and anti-proliferative effects. (Invest Ophthalmol Vis Sci. 2012; 53: 65416556) DOI:10.1167/iovs.11-9241
引用
收藏
页码：6541 / 6556
页数：16
相关论文
共 60 条
[1]   INCREASED VASCULAR ENDOTHELIAL GROWTH-FACTOR LEVELS IN THE VITREOUS OF EYES WITH PROLIFERATIVE DIABETIC-RETINOPATHY [J].
ADAMIS, AP ;
MILLER, JW ;
BERNAL, MT ;
DAMICO, DJ ;
FOLKMAN, J ;
YEO, TK ;
YEO, KT .
AMERICAN JOURNAL OF OPHTHALMOLOGY, 1994, 118 (04) :445-450
[2]   SUPPRESSION OF RETINAL NEOVASCULARIZATION IN-VIVO BY INHIBITION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR (VEGF) USING SOLUBLE VEGF-RECEPTOR CHIMERIC PROTEINS [J].
AIELLO, LP ;
PIERCE, EA ;
FOLEY, ED ;
TAKAGI, H ;
CHEN, H ;
RIDDLE, L ;
FERRARA, N ;
KING, GL ;
SMITH, LEH .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (23) :10457-10461
[3]   Diagnosis and Classification of Diabetes Mellitus [J].
DIABETES CARE, 2010, 33 :S62-S69
[4]   Diabetic retinopathy - Seeing beyond glucose-induced microvascular disease [J].
Antonetti, David A. ;
Barber, Alistair J. ;
Bronson, Sarah K. ;
Freeman, Willard M. ;
Gardner, Thomas W. ;
Jefferson, Leonard S. ;
Kester, Mark ;
Kimball, Scot R. ;
Krady, J. Kyle ;
LaNoue, Kathryn F. ;
Norbury, Christopher C. ;
Quinn, Patrick G. ;
Sandirasegarane, Lakshman ;
Simpson, Ian A. .
DIABETES, 2006, 55 (09) :2401-2411
[5]   Heme oxygenase-1 induced in Muller cells plays a protective role in retinal ischemia-reperfusion injury in rats [J].
Arai-Gaun, S ;
Katai, N ;
Kikuchi, T ;
Kurokawa, T ;
Ohta, K ;
Yoshimura, N .
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2004, 45 (11) :4226-4232
[6]   Hypoxia and Oxidative Stress in the Causation of Diabetic Retinopathy [J].
Arden, Geoffrey B. ;
Sivaprasad, Sobha .
CURRENT DIABETES REVIEWS, 2011, 7 (05) :291-304
[7]   Curcurnin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element [J].
Balogun, E ;
Hoque, M ;
Gong, PF ;
Killeen, E ;
Green, CJ ;
Foresti, R ;
Alam, J ;
Motterlini, R .
BIOCHEMICAL JOURNAL, 2003, 371 :887-895
[8]   Muller cells in the healthy and diseased retina [J].
Bringmann, Andreas ;
Pannicke, Thomas ;
Grosche, Jens ;
Francke, Mike ;
Wiedemann, Peter ;
Skatchkov, Serguei N. ;
Osborne, Neville N. ;
Reichenbach, Andreas .
PROGRESS IN RETINAL AND EYE RESEARCH, 2006, 25 (04) :397-424
[9]  
Calkins MJ, 2009, ANTIOXID REDOX SIGN, V11, P497, DOI 10.1089/ARS.2008.2242
[10]   Upregulation of heme oxygenase-1 by brazilin via the phosphatidylinositol 3-kinase/Akt and ERK pathways and its protective effect against oxidative injury [J].
Choi, Byung-Min ;
Kim, Bok-Ryang .
EUROPEAN JOURNAL OF PHARMACOLOGY, 2008, 580 (1-2) :12-18
123456