Increased Osteopontin Levels in the Vitreous of Patients with Diabetic Retinopathy

Kase, Satoru; Yokoi, Masahiko; Saito, Wataru; Furudate, Naoki; Ohgami, Kazuhiro; Kitamura, M.; Yoshida, Kazuhiko; Kase, Manabu; Ohno, Shigeaki; Uede, Toshimitsu

doi:10.1159/000102936

Cited by 40 publications

(37 citation statements)

References 26 publications

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“…However, a significant increase in the level of osteopontin was observed under HG but not normal or osmotic control. This is consistent with the increased levels of osteopontin detected in vitreous of diabetic patients and its association with vascular complications of diabetes (35,62,63).…”

Section: Alterations In Expression Of Ecm Proteins and Their Receptorsupporting

confidence: 88%

“…Increased production of fibronectin and its deposition in the basement membrane of retinal vessels during diabetes, and retinal EC under HG conditions, have been previously reported (6,44,47,53,54). The ECM protein osteopontin is a proinflammatory cytokine implicated in the chemoattraction of monocytes and the development of atherosclerosis, as well as vascular complications of diabetes (35,36,46,56). The ␣ v ␤ 3 -integrin is most important for osteopontin prosurvival effects in EC (56).…”

Section: Discussionmentioning

confidence: 92%

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High glucose promotes retinal endothelial cell migration through activation of Src, PI3K/Akt1/eNOS, and ERKs

Huang¹,

Sheibani²

2008

American Journal of Physiology-Cell Physiology

105

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Here we determined the impact of high glucose on mouse retinal EC function in vitro. High glucose significantly enhanced the migration of retinal EC without impacting their proliferation, apoptosis, adhesion, and capillary morphogenesis. The enhanced migration of retinal EC under high glucose was reversed in the presence of the antioxidant N-acetylcysteine, suggesting increased oxidative stress under highglucose conditions. Retinal EC under high-glucose conditions also expressed increased levels of fibronectin, osteopontin, and ␣ v␤3-integrin, and reduced levels of thrombospondin-1. These changes were concomitant with sustained activation of the downstream prosurvival and promigratory signaling pathways, including Src kinase, phosphatidylinositol 3-kinase/Akt1/endothelial nitric oxide synthase, and ERKs. The sustained activation of these signaling pathways was essential for enhanced migration of retinal EC under high-glucose conditions. Together, our results indicate the exposure of retinal EC to high glucose promotes a promigratory phenotype. Thus alterations in the proangiogenic properties of retinal EC during diabetes may contribute to the development and pathogenesis of diabetic retinopathy. diabetic retinopathy; angiogenesis; integrins; extracellular matrix; thrombospondin; osteopontin RETINAL MICROVASCULAR COMPLICATIONS and pathological neovascularization are the major causes of blindness in patients with diabetes (16,20). How these vascular dysfunctions are brought about by diabetes and what their functional consequences are in retinal functions have been the subject of numerous studies. A causal link between diabetic hyperglycemia and the development of retinal vascular complications has been established, such that tight glucose control in diabetic patients reduces the progression of the disease (64). Therefore, hyperglycemia has been implicated in the activation of numerous key mechanisms/pathways, including oxidative and nitrative stress (8, 49), advanced glycation end products (21), and aldose reductase (10, 60), which, in concert, contribute to retinal vascular dysfunctions and diabetic retinopathies. Understanding how these pathways are activated and/or impact retinal vascular cell function under hyperglycemic conditions will aid in the development of new modalities to halt the development and progression of the disease.The effects of high-glucose concentration on proliferation and survival of various types of endothelial cells (EC), including human umbilical vein EC (HUVEC) (48, 66), human pulmonary artery EC (45), human dermal microvascular EC (34), aortic EC (22), and retinal EC (42, 55), have been previously demonstrated. However, the report of conflicting results in EC properties under high glucose (25,26,59), perhaps through different intracellular signaling pathways, makes the interpretation of these results difficult. These conflicting reports may also be explained, at least in part, by the differences in species, tissues of origin, macro-vs. microvascular EC, or experimental conditions util...

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Section: Alterations In Expression Of Ecm Proteins and Their Receptorsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 92%

High glucose promotes retinal endothelial cell migration through activation of Src, PI3K/Akt1/eNOS, and ERKs

Huang¹,

Sheibani²

2008

American Journal of Physiology-Cell Physiology

105

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“…Moreover, osteopontin, a proinflammatory cytokine, was detected in both PDR and control samples, and has diverse functions such as cell adhesion, immunomodulation, and angiogenesis. Vitreous osteopontin levels have been reported to be higher in patients with DR than in normal controls, which suggests that osteopontin plays a role in the pathogenesis of DR [46]. Moreover, angiotensinogen, which is cleaved by renin to form angiotensin I, was detected in the vitreous of PDR and control patients in the present study, and the rennin-angiotensin system (RAS) was suggested to be locally activated in PDR eyes.…”

Section: Pathogenic Implications Of Identified Proteins On Pdrsupporting

confidence: 49%

Profiling of vitreous proteomes from proliferative diabetic retinopathy and nondiabetic patients

Kim

et al. 2007

Proteomics

133

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Diabetes can lead to serious microvascular complications like proliferative diabetic retinopathy (PDR), which is the leading cause of blindness in adults. The proteomic changes that occur during PDR cannot be measured in the human retina for ethical reasons, but could be reflected by proteomic changes in vitreous humor. Thus, we considered that comparisons between the proteome profiles of the vitreous humors of PDR and nondiabetic controls could lead to the discovery of novel pathogenic proteins and clinical biomarkers. In this study, the authors used several proteomic methods to comprehensively examine vitreous humor proteomes of PDR patients and nondiabetic controls. These methods included immunoaffinity subtraction (IS)/2-DE/ MALDI-MS, nano-LC-MALDI-MS/MS, and nano-LC-ESI-MS/MS. The identified proteins were subjected to the Trans-Proteomic Pipeline validation process. Resultantly, 531 proteins were identified, i.e., 415 and 346 proteins were identified in PDR and nondiabetic control vitreous humor samples, respectively, and of these 531 proteins, 240 were identified for the first time in this study. The PDR vitreous proteome was also found to contain many proteins possibly involved in the pathogenesis of PDR. The proteins described provide the most comprehensive proteome listing in the vitreous humor samples of PDR and nondiabetic control patients.

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“…It has been demonstrated that levels of some inflammatory cytokines were significantly higher in the vitreous of patients with proliferative diabetic retinopathy (PDR) than in those of non-diabetic patients (18). This suggests that the inflammatory reaction takes place in the retina during the development of diabetic retinopathy.…”

Section: Introductionmentioning

confidence: 99%

Increased expression of αA-crystallin in human diabetic eye

Kase

Ishida²,

Rao³

2011

Int J Mol Med

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Abstract. We recently demonstrated that αA-crystallin, a molecular chaperone, protected photoreceptors from apoptotic signals in intraocular inflammation. Advanced glycation end product (AGE) plays an important role in the progression of diabetic retinopathy. The aim of this study was to examine the expression of α-crystallins and apoptosis in human diabetic retina, and to analyze α-crystallin up-regulation in murine eyes after AGE stimulation. Eight eye globes were obtained from postmortem donors. Six out of the eight had a medical history of diabetes mellitus, while two were without diabetes. Formalinfixed, paraffin-embedded tissue sections were subjected to H&E staining and immunohistochemistry with anti-αA and αB-crystallins, anti-AGE and receptor for AGE (RAGE) antibodies. Apoptotic cells were detected by the TUNEL assay. Recom binant AGE protein was injected into the vitreous of adult murine eyes, and the posterior eyecups were excised 4 days after the administration. Western blot analyses and quantitative real-time PCR were performed to evaluate the alteration of α-crystallin expression. Histopathology revealed no remarkable differences between diabetic and non-diabetic retinas. Immunoreactivity for αA-crystallin was predominantly detected in the diabetic retina, whereas αB-crystallin expression was relatively low. AGE immunoreactivity was highly detected in diabetic retina and the vitreous, whilst immunoreactivity for RAGE was less marked. TUNEL-positive apoptotic cells were occasionally observed in photoreceptors of the diabetic retina, whereas cytoplasmic immunoreactivity for αA-crystallin was relatively low. αA-crystallin expression was up-regulated, and αB-crystallin was down-regulated in murine posterior eyecups exposed to AGE protein. The mRNA levels of αA-crystallin were significantly up-regu lated, whereas those of αB-crystallin remained unchanged after AGE stimulation. Thus, αA-crystallin and AGE were highly expressed in human diabetic retina. αA-crystallin responded to AGE accumulation, which may contribute to the protection of photoreceptors against AGE-related retinal tissue injury.

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Increased Osteopontin Levels in the Vitreous of Patients with Diabetic Retinopathy

Cited by 40 publications

References 26 publications

High glucose promotes retinal endothelial cell migration through activation of Src, PI3K/Akt1/eNOS, and ERKs

High glucose promotes retinal endothelial cell migration through activation of Src, PI3K/Akt1/eNOS, and ERKs

Profiling of vitreous proteomes from proliferative diabetic retinopathy and nondiabetic patients

Increased expression of αA-crystallin in human diabetic eye

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