The Experts below are selected from a list of 726 Experts worldwide ranked by ideXlab platform
James M Dominguez - One of the best experts on this subject based on the ideXlab platform.
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adeno associated virus overexpression of angiotensin converting enzyme 2 reverses diabetic retinopathy in type 1 diabetes in mice
American Journal of Pathology, 2016Co-Authors: James M Dominguez, Ping Hu, Sergio Caballero, Leni Moldovan, Amrisha Verma, Gavin Y Oudit, Qiuhong Li, Maria B GrantAbstract:Angiotensin-converting enzyme (ACE)-2 is the primary enzyme of the vasoprotective axis of the renin angiotensin system that regulates the classic renin angiotensin system axis. We aimed to determine whether local retinal overexpression of adenoassociated virus (AAV)–ACE2 prevents or reverses diabetic retinopathy. Green fluorescent protein ( GFP )–chimeric mice were generated to distinguish resident (retinal) from infiltrating bone marrow–derived inflammatory cells and were made diabetic using streptozotocin injections. Retinal digestion using trypsin was performed and acellular capillaries enumerated. Capillary occlusion by GFP + cells was used to measure Leukostasis. Overexpression of ACE2 prevented (prevention cohort: untreated diabetic, 11.3 ± 1.4; ACE2 diabetic, 6.4 ± 0.9 per mm 2 ) and partially reversed (reversal cohort: untreated diabetic, 15.7 ± 1.9; ACE2 diabetic, 6.5 ± 1.2 per mm 2 ) the diabetes-associated increase of acellular capillaries and the increase of infiltrating inflammatory cells into the retina (F4/80 + ) (prevention cohort: untreated diabetic, 24.2 ± 6.7; ACE2 diabetic, 2.5 ± 1.6 per mm 2 ; reversal cohort: untreated diabetic, 56.8 ± 5.2; ACE2 diabetic, 5.6 ± 2.3 per mm 2 ). In both study cohorts, intracapillary bone marrow–derived cells, indicative of Leukostasis, were only observed in diabetic animals receiving control AAV injections. These results indicate that diabetic retinopathy, and possibly other diabetic microvascular complications, can be prevented and reversed by locally restoring the balance between the classic and vasoprotective renin angiotensin system.
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adeno associated virus overexpression of angiotensin converting enzyme 2 reverses diabetic retinopathy in type 1 diabetes in mice
American Journal of Pathology, 2016Co-Authors: James M Dominguez, Sergio Caballero, Leni Moldovan, Amrisha Verma, Gavin Y Oudit, Maria B GrantAbstract:Angiotensin-converting enzyme (ACE)-2 is the primary enzyme of the vasoprotective axis of the renin angiotensin system that regulates the classic renin angiotensin system axis. We aimed to determine whether local retinal overexpression of adenoassociated virus (AAV)–ACE2 prevents or reverses diabetic retinopathy. Green fluorescent protein ( GFP )–chimeric mice were generated to distinguish resident (retinal) from infiltrating bone marrow–derived inflammatory cells and were made diabetic using streptozotocin injections. Retinal digestion using trypsin was performed and acellular capillaries enumerated. Capillary occlusion by GFP + cells was used to measure Leukostasis. Overexpression of ACE2 prevented (prevention cohort: untreated diabetic, 11.3 ± 1.4; ACE2 diabetic, 6.4 ± 0.9 per mm 2 ) and partially reversed (reversal cohort: untreated diabetic, 15.7 ± 1.9; ACE2 diabetic, 6.5 ± 1.2 per mm 2 ) the diabetes-associated increase of acellular capillaries and the increase of infiltrating inflammatory cells into the retina (F4/80 + ) (prevention cohort: untreated diabetic, 24.2 ± 6.7; ACE2 diabetic, 2.5 ± 1.6 per mm 2 ; reversal cohort: untreated diabetic, 56.8 ± 5.2; ACE2 diabetic, 5.6 ± 2.3 per mm 2 ). In both study cohorts, intracapillary bone marrow–derived cells, indicative of Leukostasis, were only observed in diabetic animals receiving control AAV injections. These results indicate that diabetic retinopathy, and possibly other diabetic microvascular complications, can be prevented and reversed by locally restoring the balance between the classic and vasoprotective renin angiotensin system.
Anthony P Adamis - One of the best experts on this subject based on the ideXlab platform.
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inhibition of diabetic Leukostasis and blood retinal barrier breakdown with a soluble form of a receptor for advanced glycation end products
Investigative Ophthalmology & Visual Science, 2007Co-Authors: Yuichi Kaji, Jonathan E. Moore, Hiroshi Yamamoto, Tomohiko Usui, Susumu Ishida, Kenji Yamashiro, Tara Moore, Yasuhiko Yamamoto, Anthony P AdamisAbstract:PURPOSE. The interaction of advanced glycation end products (AGEs) with their receptors is hypothesized to be involved in the development of diabetic retinopathy. In the present study, the role of an AGE receptor, RAGE, was investigated in the development of diabetic retinopathy in vivo. METHODS. C57/BJ6 and RAGE-transgenic mice that carried human RAGE genetic DNA under the control of the murine flk-1 promoter were made diabetic with streptozocin. Three months after the onset of diabetes, the soluble form of RAGE (sRAGE) or mouse serum albumin was injected intraperitoneally at 100 g/d for 14 consecutive days. After the final injection, blood‐retinal barrier breakdown, retinal Leukostasis, expression of VEGF and ICAM-1, and expression of RAGE in the retina were investigated. RESULTS. Blood‐retinal barrier breakdown and increased Leukostasis were associated with the experimental diabetes in the C57/BJ6 mice. These changes were significantly augmented in RAGE-transgenic mice. The blood‐retinal barrier breakdown and Leukostasis in the diabetic C57/BJ6 and RAGE-transgenic mice were accompanied by increased expression of VEGF and ICAM-1 in the retina. The systemic administration of sRAGE significantly inhibited blood‐retinal barrier breakdown, Leukostasis, and expression of ICAM-1 in the retina in both the diabetic C57/BJ6 and RAGE-transgenic mice. The expression of RAGE was slightly increased in the retinal vessels in diabetic or RAGE-transgenic mice. Furthermore, a strong induction of RAGE was observed in the retinal vessels of diabetic RAGEtransgenic mice. CONCLUSIONS. This study further demonstrates the role of the AGEs and RAGE axis in blood‐retinal barrier breakdown and the retinal Leukostasis, which are characteristic clinical symptoms of diabetic retinopathy. Furthermore, these data demonstrate that blocking AGE bioactivity may be effective for the treatment of diabetic retinopathy. (Invest Ophthalmol Vis Sci. 2007;48:858‐865) DOI:10.1167/iovs.06-0495 D iabetic retinopathy is a leading cause of blindness and visual impairment in the developed world and its incidence is increasing. Advances have been made in the treatment of diabetic retinopathy; however, the number of visually impaired and blind patients with the disease continues to increase. Therefore, it is important to understand the pathogenic mechanisms underlying diabetic retinopathy so that novel, more effective therapeutic and preventative strategies can be developed. Diabetes induces various complications, including nephropathy, neuropathy, retinopathy, and microangiopathy. The clinical complications vary considerably; however, they may share common underlying mechanisms. Potential biochemical path
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characterization of retinal Leukostasis and hemodynamics in insulin resistance and diabetes role of oxidants and protein kinase c activation
Diabetes, 2003Co-Authors: Toru Abiko, Atsuko Abiko, Brett Shoelson, Naoichi Horio, Allen C Clermont, J. Takahashi, Anthony P Adamis, George L King, Sven-erik BursellAbstract:Increases in Leukostasis/monocyte adhesion to the capillary endothelium (Leukostasis) and decreases in retinal blood flow may be causally associated and are implicated in the pathogenesis of diabetic retinopathy. In this study, we demonstrate that increases in Leukostasis are observed in insulin-resistant states without diabetes, whereas decreases in retinal blood flow require diabetes and hyperglycemia. Microimpaction studies using beads mimicking retinal capillary obstruction by leukocytes did not affect retinal blood flow. In diabetic rats, treatment with the antioxidant α-lipoic acid normalized the amount of Leukostasis but not retinal blood flow. In contrast, treatment with d-α-tocopherol and protein kinase-C β-isoform inhibition (LY333531) prevented the increases in Leukostasis and decreases in retinal blood flow in diabetic rats. Serum hydroxyperoxide, a marker of oxidative stress, was increased in diabetic rats, but normalized by treatment with antioxidants α-lipoic acid and d-α-tocopherol and, surprisingly, PKC β-isoform inhibition. These findings suggest that Leukostasis is associated with endothelial dysfunction, insulin resistance, and oxidative stress but is not related to retinal blood flow and is not sufficient to cause diabetic-like retinopathy. Moreover, treatment with PKC β inhibition is effective to normalize diabetes or hyperglycemia-induced PKC β-isoform activation and oxidative stress.
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vascular endothelial growth factor vegf induced retinal vascular permeability is mediated by intercellular adhesion molecule 1 icam 1
American Journal of Pathology, 2000Co-Authors: Kazuaki Miyamoto, Samer Khosrof, Sven-erik Bursell, Yuichiro Ogura, Lloyd Paul Aiello, Anthony P Adamis, Yasufumi MoromizatoAbstract:Two prominent vascular endothelial growth factor (VEGF)-induced retinal effects are vascular permeability and capillary nonperfusion. The mechanisms by which these effects occur are not completely known. Using a rat model, we show that intravitreous injections of VEGF precipitate an extensive retinal leukocyte stasis (Leukostasis) that coincides with enhanced vascular permeability and capillary nonperfusion. The Leukostasis is accompanied by the up-regulation of intercellular adhesion molecule-1 expression in the retina. The inhibition of intercellular adhesion molecule-1 bioactivity with a neutralizing antibody prevents the permeability and Leukostasis increases by 79% and 54%, respectively. These data are the first to demonstrate that a nonendothelial cell type contributes to VEGF-induced vascular permeability. Additionally, they identify a potential mechanism for VEGF-induced retinal capillary nonperfusion.
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prevention of Leukostasis and vascular leakage in streptozotocin induced diabetic retinopathy via intercellular adhesion molecule 1 inhibition
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Kazuaki Miyamoto, Samer Khosrof, Richard M Rohan, Sven-erik Bursell, Allen C Clermont, Toshinori Murata, Yuichiro Ogura, Lloyd Paul Aiello, Anthony P AdamisAbstract:Diabetic retinopathy is a leading cause of adult vision loss and blindness. Much of the retinal damage that characterizes the disease results from retinal vascular leakage and nonperfusion. This study shows that diabetic retinal vascular leakage and nonperfusion are temporally and spatially associated with retinal leukocyte stasis (Leukostasis) in the rat model of streptozotocin-induced diabetes. Retinal Leukostasis increases within days of developing diabetes and correlates with the increased expression of retinal intercellular adhesion molecule-1 (ICAM-1). ICAM-1 blockade with a mAb prevents diabetic retinal Leukostasis and vascular leakage by 48.5% and 85.6%, respectively. These data identify the causal role of leukocytes in the pathogenesis of diabetic retinopathy and establish the potential utility of ICAM-1 inhibition as a therapeutic strategy for the prevention of diabetic retinopathy.
Maria B Grant - One of the best experts on this subject based on the ideXlab platform.
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adeno associated virus overexpression of angiotensin converting enzyme 2 reverses diabetic retinopathy in type 1 diabetes in mice
American Journal of Pathology, 2016Co-Authors: James M Dominguez, Ping Hu, Sergio Caballero, Leni Moldovan, Amrisha Verma, Gavin Y Oudit, Qiuhong Li, Maria B GrantAbstract:Angiotensin-converting enzyme (ACE)-2 is the primary enzyme of the vasoprotective axis of the renin angiotensin system that regulates the classic renin angiotensin system axis. We aimed to determine whether local retinal overexpression of adenoassociated virus (AAV)–ACE2 prevents or reverses diabetic retinopathy. Green fluorescent protein ( GFP )–chimeric mice were generated to distinguish resident (retinal) from infiltrating bone marrow–derived inflammatory cells and were made diabetic using streptozotocin injections. Retinal digestion using trypsin was performed and acellular capillaries enumerated. Capillary occlusion by GFP + cells was used to measure Leukostasis. Overexpression of ACE2 prevented (prevention cohort: untreated diabetic, 11.3 ± 1.4; ACE2 diabetic, 6.4 ± 0.9 per mm 2 ) and partially reversed (reversal cohort: untreated diabetic, 15.7 ± 1.9; ACE2 diabetic, 6.5 ± 1.2 per mm 2 ) the diabetes-associated increase of acellular capillaries and the increase of infiltrating inflammatory cells into the retina (F4/80 + ) (prevention cohort: untreated diabetic, 24.2 ± 6.7; ACE2 diabetic, 2.5 ± 1.6 per mm 2 ; reversal cohort: untreated diabetic, 56.8 ± 5.2; ACE2 diabetic, 5.6 ± 2.3 per mm 2 ). In both study cohorts, intracapillary bone marrow–derived cells, indicative of Leukostasis, were only observed in diabetic animals receiving control AAV injections. These results indicate that diabetic retinopathy, and possibly other diabetic microvascular complications, can be prevented and reversed by locally restoring the balance between the classic and vasoprotective renin angiotensin system.
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adeno associated virus overexpression of angiotensin converting enzyme 2 reverses diabetic retinopathy in type 1 diabetes in mice
American Journal of Pathology, 2016Co-Authors: James M Dominguez, Sergio Caballero, Leni Moldovan, Amrisha Verma, Gavin Y Oudit, Maria B GrantAbstract:Angiotensin-converting enzyme (ACE)-2 is the primary enzyme of the vasoprotective axis of the renin angiotensin system that regulates the classic renin angiotensin system axis. We aimed to determine whether local retinal overexpression of adenoassociated virus (AAV)–ACE2 prevents or reverses diabetic retinopathy. Green fluorescent protein ( GFP )–chimeric mice were generated to distinguish resident (retinal) from infiltrating bone marrow–derived inflammatory cells and were made diabetic using streptozotocin injections. Retinal digestion using trypsin was performed and acellular capillaries enumerated. Capillary occlusion by GFP + cells was used to measure Leukostasis. Overexpression of ACE2 prevented (prevention cohort: untreated diabetic, 11.3 ± 1.4; ACE2 diabetic, 6.4 ± 0.9 per mm 2 ) and partially reversed (reversal cohort: untreated diabetic, 15.7 ± 1.9; ACE2 diabetic, 6.5 ± 1.2 per mm 2 ) the diabetes-associated increase of acellular capillaries and the increase of infiltrating inflammatory cells into the retina (F4/80 + ) (prevention cohort: untreated diabetic, 24.2 ± 6.7; ACE2 diabetic, 2.5 ± 1.6 per mm 2 ; reversal cohort: untreated diabetic, 56.8 ± 5.2; ACE2 diabetic, 5.6 ± 2.3 per mm 2 ). In both study cohorts, intracapillary bone marrow–derived cells, indicative of Leukostasis, were only observed in diabetic animals receiving control AAV injections. These results indicate that diabetic retinopathy, and possibly other diabetic microvascular complications, can be prevented and reversed by locally restoring the balance between the classic and vasoprotective renin angiotensin system.
G Scicli - One of the best experts on this subject based on the ideXlab platform.
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role of nadph oxidase and ang ii in diabetes induced retinal Leukostasis
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2007Co-Authors: Ping Chen, Paul A Edwards, Gary L Trick, G ScicliAbstract:We studied whether angiotensin II (ANG II) via superoxide may contribute to retinal Leukostasis and thus to the pathogenesis of retinopathies. We studied: 1) whether intravitreal ANG II induces ret...
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role of angiotensin ii in retinal Leukostasis in the diabetic rat
Experimental Eye Research, 2006Co-Authors: Ping Chen, David Dahl, Paul A Edwards, Joseph D Fenstermacher, G ScicliAbstract:Abstract To study if the endogenous renin–angiotensin system affects diabetic retinal Leukostasis, rats with streptozotocin-induced diabetes were treated with an ACE inhibitor (ramipril), an angiotensin II AT 1 receptor antagonist (losartan) and the Ca channel blocker, (nifedipine). In the diabetic rats, these drug treatments reduced systolic blood pressure by ∼16 mmHg but did not change blood glucose. After 2 weeks, the rats were examined for retinal Leukostasis in vivo with a scanning laser ophthalmoscope (SLO). Retinal Leukostasis, which was defined as no movement of arrested leukocytes over 2 min, was markedly higher in diabetic rats than normal controls ( P P P
Sergio Caballero - One of the best experts on this subject based on the ideXlab platform.
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adeno associated virus overexpression of angiotensin converting enzyme 2 reverses diabetic retinopathy in type 1 diabetes in mice
American Journal of Pathology, 2016Co-Authors: James M Dominguez, Ping Hu, Sergio Caballero, Leni Moldovan, Amrisha Verma, Gavin Y Oudit, Qiuhong Li, Maria B GrantAbstract:Angiotensin-converting enzyme (ACE)-2 is the primary enzyme of the vasoprotective axis of the renin angiotensin system that regulates the classic renin angiotensin system axis. We aimed to determine whether local retinal overexpression of adenoassociated virus (AAV)–ACE2 prevents or reverses diabetic retinopathy. Green fluorescent protein ( GFP )–chimeric mice were generated to distinguish resident (retinal) from infiltrating bone marrow–derived inflammatory cells and were made diabetic using streptozotocin injections. Retinal digestion using trypsin was performed and acellular capillaries enumerated. Capillary occlusion by GFP + cells was used to measure Leukostasis. Overexpression of ACE2 prevented (prevention cohort: untreated diabetic, 11.3 ± 1.4; ACE2 diabetic, 6.4 ± 0.9 per mm 2 ) and partially reversed (reversal cohort: untreated diabetic, 15.7 ± 1.9; ACE2 diabetic, 6.5 ± 1.2 per mm 2 ) the diabetes-associated increase of acellular capillaries and the increase of infiltrating inflammatory cells into the retina (F4/80 + ) (prevention cohort: untreated diabetic, 24.2 ± 6.7; ACE2 diabetic, 2.5 ± 1.6 per mm 2 ; reversal cohort: untreated diabetic, 56.8 ± 5.2; ACE2 diabetic, 5.6 ± 2.3 per mm 2 ). In both study cohorts, intracapillary bone marrow–derived cells, indicative of Leukostasis, were only observed in diabetic animals receiving control AAV injections. These results indicate that diabetic retinopathy, and possibly other diabetic microvascular complications, can be prevented and reversed by locally restoring the balance between the classic and vasoprotective renin angiotensin system.
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adeno associated virus overexpression of angiotensin converting enzyme 2 reverses diabetic retinopathy in type 1 diabetes in mice
American Journal of Pathology, 2016Co-Authors: James M Dominguez, Sergio Caballero, Leni Moldovan, Amrisha Verma, Gavin Y Oudit, Maria B GrantAbstract:Angiotensin-converting enzyme (ACE)-2 is the primary enzyme of the vasoprotective axis of the renin angiotensin system that regulates the classic renin angiotensin system axis. We aimed to determine whether local retinal overexpression of adenoassociated virus (AAV)–ACE2 prevents or reverses diabetic retinopathy. Green fluorescent protein ( GFP )–chimeric mice were generated to distinguish resident (retinal) from infiltrating bone marrow–derived inflammatory cells and were made diabetic using streptozotocin injections. Retinal digestion using trypsin was performed and acellular capillaries enumerated. Capillary occlusion by GFP + cells was used to measure Leukostasis. Overexpression of ACE2 prevented (prevention cohort: untreated diabetic, 11.3 ± 1.4; ACE2 diabetic, 6.4 ± 0.9 per mm 2 ) and partially reversed (reversal cohort: untreated diabetic, 15.7 ± 1.9; ACE2 diabetic, 6.5 ± 1.2 per mm 2 ) the diabetes-associated increase of acellular capillaries and the increase of infiltrating inflammatory cells into the retina (F4/80 + ) (prevention cohort: untreated diabetic, 24.2 ± 6.7; ACE2 diabetic, 2.5 ± 1.6 per mm 2 ; reversal cohort: untreated diabetic, 56.8 ± 5.2; ACE2 diabetic, 5.6 ± 2.3 per mm 2 ). In both study cohorts, intracapillary bone marrow–derived cells, indicative of Leukostasis, were only observed in diabetic animals receiving control AAV injections. These results indicate that diabetic retinopathy, and possibly other diabetic microvascular complications, can be prevented and reversed by locally restoring the balance between the classic and vasoprotective renin angiotensin system.