Protective role of pigment epithelium‐derived factor (PEDF) in early phase of experimental diabetic retinopathy

Yoshida, Yumiko; Yamagishi, Sho‐ichi; Matsui, Takanori; Jinnouchi, Yuko; Fukami, Kei; Imaizumi, Tsutomu; Yamakawa, Ryoji

doi:10.1002/dmrr.1007

Cited by 100 publications

(83 citation statements)

References 27 publications

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“…The results were consistent with our previous observations showing that PEDF levels were decreased in damaged vascular tissues such as balloon-injured arteries, diabetic retinas, and glomeruli with Adriamycin-associated nephrotic syndrome in rats. 23,25,29 In contrast to the infarcted LV areas, we found that PEDF levels were significantly increased in cardiomyocytes of noninfarcted LV areas 4 and 8 weeks after AMI (Figure 1, B and C). Although we did not clarify here the molecular mecha- LV lesions.…”

Section: Discussionmentioning

confidence: 80%

“…once daily in our model because we have previously found that (1) intravenous administration of 3.3 to 10 g PEDF/100 g b.wt. once a day exerts antithrombogenic, antipermeability, and anti-inflammatory effects in rats 16,23,24,29 ; (2) the peak concentration of circulating PEDF level is obtained at 2 hours after the 10 g PEDF injection/100 g b.wt. ; and (3) its level is increased to about 2-fold of basal level (from about 200 ng/ml to 400 ng/ml) in SD rats at 8 weeks of age.…”

Section: Discussionmentioning

confidence: 99%

“…14 -21 PEDF also has been shown to reduce vascular inflammation and hyperpermeability in diabetic rats, suppress thrombosis in a rat model of arterial occlusive thrombus formation, and prevent balloon injury-induced neointimal hyperplasia in rats. [22][23][24][25] These observations led us to speculate that PEDF could exert beneficial effects on LV remodeling by suppressing oxidative stress generation and inflammatory reactions in AMI. However, the protective role of PEDF against LV remodeling after AMI remains unknown.…”

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confidence: 99%

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Administration of Pigment Epithelium-Derived Factor Inhibits Left Ventricular Remodeling and Improves Cardiac Function in Rats with Acute Myocardial Infarction

Ueda

Yamagishi

Matsui

et al. 2011

The American Journal of Pathology

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Oxidative stress and inflammation are involved in cardiac remodeling after acute myocardial infarction (AMI). We have found that pigment epithelium-derived factor (PEDF) inhibits vascular inflammation through its anti-oxidative properties. However, effects of PEDF on cardiac remodeling after AMI remain unknown. We investigated whether PEDF could inhibit left ventricular remodeling and improve cardiac function in rats with AMI. AMI was induced in 8-weekold Sprague-Dawley rats by ligation of the left ascending coronary artery. Rats were treated intravenously with vehicle or 10 g PEDF/100 g b.wt. every day for up to 2 weeks after AMI. Each rat was followed until 16 weeks of age. PEDF levels in infarcted areas and serum were significantly decreased at 1 week after AMI and remained low during the observational periods. PEDF administration inhibited apoptotic cell death and oxidative stress generation around the infarcted areas at 2 and 8 weeks after AMI. Further, PEDF injection suppressed cardiac fibrosis by reducing transforming growth factor-␤ and type III collagen expression, improved left ventricular ejection fraction, ameliorated diastolic dysfunction, and inhibited the increase in left ventricular mass index at 8 weeks after AMI. The present study demonstrated that PEDF could inhibit tissue remodeling and improve cardiac function in AMI rats. Substitution of PEDF may be a novel therapeutic strategy for cardiac remodeling after AMI.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Administration of Pigment Epithelium-Derived Factor Inhibits Left Ventricular Remodeling and Improves Cardiac Function in Rats with Acute Myocardial Infarction

Ueda

Yamagishi

Matsui

et al. 2011

The American Journal of Pathology

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“…The molecular link between two well-documented early hallmarks of diabetic retinopathy, i.e. accelerated neuronal death and vascular permeability, remains obscure [1][2][3][10][11][12][13]. While proinflammatory cytokines are known to activate Rho family kinases leading to actin cytoskeleton rearrangement and cell permeability in vasculature, Rho family members are also essential regulators of neuronal survival in the nervous system, as reviewed by Linseman and Loucks [14].…”

Section: Introductionmentioning

confidence: 99%

Diabetes-induced peroxynitrite impairs the balance of pro-nerve growth factor and nerve growth factor, and causes neurovascular injury

Al‐Gayyar²,

et al. 2010

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Aims/hypothesis Diabetic retinopathy, the leading cause of blindness in working-age Americans, is characterised by reduced neurotrophic support and increased proinflammatory cytokines, resulting in neurotoxicity and vascular permeability. We sought to elucidate how oxidative stress impairs homeostasis of nerve growth factor (NGF) and its precursor, proform of NGF (proNGF), to cause neurovascular dysfunction in the eye of diabetic patients. Methods Levels of NGF and proNGF were examined in samples from human patients, from retinal Müller glial cell line culture cells and from streptozotocin-induced diabetic animals treated with and without atorvastatin (10 mg/kg daily, per os) or 5,10,15,20-tetrakis (4-sulfonatophenyl) porphyrinato iron (III) chloride (FeTPPs) (15 mg/kg daily, i.p.) for 4 weeks. Neuronal death and vascular permeability were assessed by TUNEL and extravasation of BSA-fluorescein. Results Diabetes-induced peroxynitrite formation impaired production and activity of matrix metalloproteinase-7 (MMP-7), which cleaves proNGF extracellularly, leading to accumulation of proNGF and reducing NGF in samples from diabetic retinopathy patients and experimental models. Treatment of diabetic animals with atorvastatin exerted similar protective effects that blocked peroxynitrite using FeTPPs, restoring activity of MMP-7 and hence the balance between proNGF and NGF. These effects were associated with preservation of blood-retinal barrier integrity, preventing neuronal cell death and blocking activation of RhoA and p38 mitogen-activated protein kinase (p38MAPK) in experimental and human samples. Conclusions/interpretation Oxidative stress plays an unrecognised role in causing accumulation of proNGF, which can activate a common pathway, RhoA/p38MAPK, to mediate neurovascular injury. Oral statin therapy shows promise for treatment of diabetic retinopathy.

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“…23 Membranes were probed with Abs against PCNA, CD31, lysosomal-associated membrane protein 2 (Mac-3) (Abcam), AGE, RAGE, VEGF, a-tubulin (Santa Cruz Biotechnology) or b-actin (Santa Cruz Biotechnology), and then immune complexes were visualized with an enhanced chemiluminescence detection system (Amersham Bioscience, Buckinghamshire, United Kingdom).…”

Section: Western Blotting Analysismentioning

confidence: 99%

DNA aptamer raised against advanced glycation end products inhibits melanoma growth in nude mice

Ojima

Matsui

Maeda

et al. 2014

Laboratory Investigation

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Epidemiological studies have suggested that diabetes is associated with an increased risk of cancer. However, the underlying molecular mechanism remains unclear. We investigated here whether DNA aptamer directed against advanced glycation end products (AGE-aptamer) inhibited melanoma growth in nude mice. G361 melanoma cells were injected intradermally into the upper flank of athymic nude mice. Mice received continuous intraperitoneal infusion (0.136 mg/day) of either AGE-aptamer (n ¼ 9) or Control-aptamer (n ¼ 8) by an osmotic mini pump. Tumor volume was measured at 4-day interval, and G361 melanoma was excised at day 43 after the aptamer treatment. We further examined the effects of AGE-aptamer on proliferation of AGE-exposed endothelial cells and G361 cells. AGE-aptamer significantly inhibited the in vivo-tumor growth of G361 melanoma. Immunohistochemical and western blotting analyses of G361 melanoma revealed that AGE-aptamer decreased expression levels of proliferating nuclear antigen, CD31 and Mac-3, markers of endothelial cells and macrophages, respectively. AGE-aptamer significantly decreased the number of tumorassociated vessels. AGE, receptor for AGE (RAGE) and vascular endothelial growth factor levels were also reduced in AGE-aptamer-treated G361 melanoma. AGE-aptamer inhibited the AGE-induced proliferation and tube formation of endothelial cells as well as the growth of G361 cells in vitro. The present findings suggest that AGE-aptamer could inhibit the AGE-RAGE axis in G361 melanoma and resultantly suppress the tumor growth in nude mice by blocking the angiogenesis. AGE-aptamer might be a novel therapeutic strategy for preventing the progression of malignant melanoma in diabetes.

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Protective role of pigment epithelium‐derived factor (PEDF) in early phase of experimental diabetic retinopathy

Cited by 100 publications

References 27 publications

Administration of Pigment Epithelium-Derived Factor Inhibits Left Ventricular Remodeling and Improves Cardiac Function in Rats with Acute Myocardial Infarction

Administration of Pigment Epithelium-Derived Factor Inhibits Left Ventricular Remodeling and Improves Cardiac Function in Rats with Acute Myocardial Infarction

Diabetes-induced peroxynitrite impairs the balance of pro-nerve growth factor and nerve growth factor, and causes neurovascular injury

DNA aptamer raised against advanced glycation end products inhibits melanoma growth in nude mice

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