Diabetic eNOS-Knockout Mice Develop Accelerated Retinopathy

Li, Qiuhong; Verma, Amrisha; Ping, Han; Nakagawa, Takahiko; Johnson, Richard J.; Grant, Maria B.; Campbell-Thompson, Martha; Jarajapu, Yagna; Lei, Bo; Hauswirth, William W.

doi:10.1167/iovs.09-5147

Cited by 100 publications

(94 citation statements)

References 56 publications

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“…Increased expression of vasoactive factors and cytokines probably plays an important role in mediating the structural and functional changes in the retina [13,14]. Although recent evidence strongly suggests that inflammation is very important in the pathogenesis of early stages of experimental DR [15,16,17], studies in humans have not found a consistent association between systemic markers of inflammation and retinopathy [16,18]. Also, it is still uncertain whether inflammation plays a crucial role in the development and progression of DR in humans.…”

Section: Pathophysiology Of Drmentioning

confidence: 99%

Epigenetic Mechanisms in the Pathogenesis of Diabetic Retinopathy

Zeng

Chen²

2014

Ophthalmologica

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Diabetic retinopathy (DR), which arises as a result of an increasing incidence of diabetes mellitus, has gradually become a common disease. Due to its complex pathogenesis, the treatment means of DR are very limited. The findings of several studies have shown that instituting tight glycemic control in diabetic patients does not immediately benefit the progression of retinopathy, and the benefits of good control persist beyond the period of good glycemic control. This has led to the concept of persistent epigenetic changes. Epigenetics has now become an increasingly important area of biomedical research. Recently, important roles of various epigenetic mechanisms have been identified in the pathogenesis of diabetes and its complications. The aim of this review is to provide an overview of the epigenetics and epigenetic mechanisms in diabetes and diabetes complications, and the focus is on the emerging evidence for aberrant epigenetic mechanisms in DR.

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Section: Pathophysiology Of Drmentioning

confidence: 99%

Epigenetic Mechanisms in the Pathogenesis of Diabetic Retinopathy

Zeng

Chen²

2014

Ophthalmologica

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“…Compared to wild diabetic mice, diabetic knockout mice develop accelerated retinopathy, characterized by the formation of abnormal acellular retinal capillaries and increased retinal vascular permeability. 91 Finally, NO inhibits exocytosis of Weibel-Palade bodies by endothelial cells. Thus, in case of decreased NO availability, more von Willebrand factor and P-selectin are released making the endothelium prothrombotic.…”

Section: Disturbances Of No Availability In Early and Advanced Diabetmentioning

confidence: 99%

The Renal Endothelium in Diabetic Nephropathy

et al. 2013

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Diabetic nephropathy is the leading cause of end-stage renal disease. Diabetes mellitus is characterized by generalized endothelial dysfunction. However, recent data also emphasizes the role of local renal endothelium dysfunction in the pathogenesis of diabetic nephropathy. Hyperglycemia triggers a complex network of signal-transduction molecules, transcription factors, and mediators that culminate in endothelial dysfunction. In the glomerulus, vascular endothelial growth factor-A (VEGF)-induced neoangiogenesis may contribute to the initial hyperfiltration and microalbuminuria due to increased filtration area and immaturity of the neovessels, respectively. However, subsequent decrease in podocytes number decreases VEGF production resulting in capillary rarefaction and decreased glomerular filtration rate (GFR). Decreased nitric oxide availability also plays a significant role in the development of advanced lesions of diabetic nephropathy through disruption of glomerular autoregulation, uncontrolled VEGF action, release of prothrombotic substances by endothelial cells and angiotensin-II-independent aldosterone production. In addition, disturbances in endothelial glycocalyx contribute to decreased permselectivity and microalbuminuria; whereas there are recent evidences that reduced glomerular fenestral endothelium leads to decreased GFR levels. Endothelial repair mechanisms are also impaired in diabetes, since circulating endothelial progenitor cells number is decreased in diabetic patients with microalbuminuria. Finally, in the context of elevated profibrotic cytokine transforming growth factor-β levels, endothelial cells also confer to the deteriorating process of fibrosis in advanced diabetic nephropathy through endothelial to mesenchymal transition.

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“…37 In brief, eyes were fixed in 4% paraformaldehyde overnight, then the retinas were dissected from eye cups, washed in water overnight, and digested in 3% trypsin (Invitrogen-Gibco, Grand Island, NY) for 3 hours at 378C. After washing with water to isolate the network of vessels from adherent retinal tissue, the vessels were mounted on a slide, allowed to dry, and stained with periodic acid Schiff-hematoxylin and eosin (Gill No.…”

Section: Trypsin Digest Preparation Of Retinal Vasculaturementioning

confidence: 99%

Tyrosine-Mutant AAV8 Delivery of HumanMERTKProvides Long-Term Retinal Preservation in RCS Rats

Deng

Dinculescu

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The absence of Mertk in RCS rats results in defective RPE phagocytosis, accumulation of outer segment (OS) debris in the subretinal space, and subsequent death of photoreceptors. Previous research utilizing Mertk gene replacement therapy in RCS rats provided proof of concept for treatment of this form of recessive retinitis pigmentosa (RP); however, the beneficial effects on retinal function were transient. In the present study, we evaluated whether delivery of a MERTK transgene using a tyrosine-mutant AAV8 capsid could lead to more robust and longer-term therapeutic outcomes than previously reported.METHODS. An AAV8 Y733F vector expressing a human MERTK cDNA driven by a RPE-selective promoter was administrated subretinally at postnatal day 2. Functional and morphological analyses were performed at 4 months and 8 months posttreatment. Retinal vasculature and Müller cell activation were analyzed by quantifying acellular capillaries and glial fibrillary acidic protein immunostaining, respectively. RESULTS.Electroretinographic responses from treated eyes were more than one-third of wild-type levels and OS were well preserved in the injection area even at 8 months. Rescue of RPE phagocytosis, prevention of retinal vasculature degeneration, and inhibition of Müller cell activation were demonstrated in the treated eyes for at least 8 months.CONCLUSIONS. This research describes a longer and much more robust functional and morphological rescue than previous studies. We also demonstrate for the first time that an AAV8 mutant capsid serotype vector has a substantial therapeutic potential for RPE-specific gene delivery. These results suggest that tyrosine-mutant AAV8 vectors hold promise for the treatment of individuals with MERTK-associated RP. (Invest Ophthalmol Vis Sci.

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Diabetic eNOS-Knockout Mice Develop Accelerated Retinopathy

Cited by 100 publications

References 56 publications

Epigenetic Mechanisms in the Pathogenesis of Diabetic Retinopathy

Epigenetic Mechanisms in the Pathogenesis of Diabetic Retinopathy

The Renal Endothelium in Diabetic Nephropathy

Tyrosine-Mutant AAV8 Delivery of HumanMERTKProvides Long-Term Retinal Preservation in RCS Rats

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