AT<sub>1</sub> receptor inhibition prevents astrocyte degeneration and restores vascular growth in oxygen‐induced retinopathy

Downie, Laura E; Pianta, Michael J.; Vingrys, Algis J.; Wilkinson-Berka, Jennifer L.; Fletcher, Erica L.

doi:10.1002/glia.20680

Cited by 81 publications

(87 citation statements)

References 77 publications

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“…ACE inhibition and ARB improve aspects of neuronal and glial damage in both situations [42], such as ameliorating losses in the electroretinogram [25,38,43] and neuronal and glial cell degeneration [44][45][46]. Our identification of renin in retinal Müller cells [2] and ganglion cells [3] is suggestive that aliskiren may influence these cell populations.…”

Section: Discussionmentioning

confidence: 97%

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

et al. 2011

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Aim/hypothesis We examined whether the renin inhibitor, aliskiren, provides similar or greater protection than ACE inhibition from non-proliferative diabetic retinopathy and from the proliferative neoangiogenesis of oxygen-induced retinopathy. Methods Transgenic (mRen-2)27 rats, which overexpress mouse renin and angiotensin in extra-renal tissues, were studied. For diabetic studies, non-diabetic, diabetic (streptozotocin, 55 mg/kg), diabetic + aliskiren (10 mg kg −1 day −1 , pump), or diabetic + lisinopril (10 mg kg −1 day −1 , drinking water) rats were evaluated over 16 weeks. For oxygeninduced retinopathy studies, rats were exposed to 80% oxygen (22 h/day) from postnatal days 0 to 11, and then room air from postnatal days 12 to 18. Aliskiren (10 or 30 mg kg −1 day −1 , pump) or lisinopril (10 mg kg −1 day −1 , drinking water) was administered during retinopathy development between postnatal days 12 and 18. Results Systolic BP in diabetic (mRen-2)27 rats was reduced with 10 mg kg −1 day −1 aliskiren, but only lisinopril normalised systolic blood pressure. In diabetic (mRen-2)27 rats, 10 mg kg −1 day −1 aliskiren and lisinopril reduced retinal acellular capillaries and leucostasis to non-diabetic levels. In oxygen-induced retinopathy, neoangiogenesis and retinal inflammation (leucostasis, ED-1 immunolabelling) were partially reduced by 10 mg kg −1 day −1 aliskiren and normalised by 30 mg kg −1 day −1 aliskiren, whereas lisinopril normalised neoangiogenesis and reduced leucostasis and ED-1 immunolabelling. Aliskiren and lisinopril normalised retinal vascular endothelial growth factor expression; however, only aliskiren reduced intercellular adhesion molecule-1 to control levels. Conclusions/interpretation Aliskiren provided similar or greater retinal protection than ACE inhibition and may be a potential treatment for diabetic retinopathy.

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Section: Discussionmentioning

confidence: 97%

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

et al. 2011

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“…In addition, telmisartan and valsartan inhibit the synaptophysin degradation that exists in the retina of a murine model of DR [30] . Moreover, valsartan is able to prolong the survival of astrocytes and reduce glial activation in the retina of rats with hypoxiainduced retinopathy [31] . Furthermore, mitochondrial oxidative stress asociated with retinal neurodegeneration has been improved by using losartan in a model of spontaneously hypertensive rats [32] .…”

Section: B4mentioning

confidence: 98%

Neurodegeneration: An early event of diabetic retinopathy

Villarroel

Ciudin²,

Hernández³

et al. 2010

WJD

124

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Diabetic retinopathy (DR) has been classically considered to be a microcirculatory disease of the retina caused by the deleterious metabolic effects of hyperglycemia per se and the metabolic pathways triggered by hyperglycemia. However, retinal neurodegeneration is already present before any microcirculatory abn ormalities can be detected in ophthalmoscopic exa mination. In other words, retinal neurodegeneration is an early event in the pathogenesis of DR which predates and participates in the microcirculatory abnormalities that occur in DR. Therefore, the study of the mechanisms that lead to neurodegeneration will be essential to identify new therapeutic targets in the early stages of DR. Elevated levels of glutamate and the overexpression of the renin angiotensinsystem play an essential role in the neurodegenerative process that occurs in diabetic retina. Among neuroprotective factors, pigment epithelial derived factor, somatostatin and erythropoietin seem to be the most relevant and these will be considered in this review. Nevertheless, it should be noted that the balance between neurotoxic and neuroprotective factors rather than levels of neu rotoxic factors alone will determine the presence or absence of retinal neurodegeneration in the diabetic eye. New strategies, based on either the delivery of neuroprotective agents or the blockade of neurotoxic factors, are currently being tested in experimental models and in clinical pilot studies. Whether these novel therapies will eventually supplement or prevent the need for laser photocoagulation or vitrectomy awaits the results of additional clinical research.

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“…Of interest was that retinal microglia also expressed the type 1 angiotensin receptor ( Figure S3), and ARB was effective in reducing microglial density in OIR, a finding that broadens the roles of the type 1 angiotensin receptor to include neovascularization, inflammation, and astrocyte survival and now microglialrelated processes. 5,7,23,38 The presence of aldosterone synthase, MR, and 11␤HSD2 in glia and ganglion cells is also of interest given the contribution of these cell types to OIR 35,36 and recent evidence that aldosterone influences ion and water channels in macroglial Müller cells. 39 In conclusion, inhibition of aldosterone synthase is equally effective at reducing the retinal neovascularization of OIR as ARB, a finding that highlights the potential of inhibiting aldosterone for the treatment of neovascular retinopathies.…”

Section: Deliyanti Et Al Aldosterone and Retinal Neovascularizationmentioning

confidence: 99%

Neovascularization Is Attenuated With Aldosterone Synthase Inhibition in Rats With Retinopathy

et al. 2012

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Abstract-Neovascularization is a hallmark feature of retinopathy of prematurity and diabetic retinopathy. Type 1 angiotensin receptor blockade reduces neovascularization in experimental retinopathy of prematurity, known as oxygen-induced retinopathy (OIR). We investigated in OIR whether inhibiting aldosterone with the aldosterone synthase inhibitor FAD286 reduced neovascularization as effectively as angiotensin receptor blockade (valsartan). OIR was induced in neonatal Sprague-Dawley rats, and they were treated with FAD286 (30 mg/kg per day), valsartan (10 mg/kg per day), or FAD286ϩvalsartan. The cellular sources of aldosterone synthase, the mineralocorticoid receptor, and 11␤-hydroxysteroid dehydrogenase 2 were evaluated in retinal cells involved in neovascularization (primary endothelial cells, pericytes, microglia, ganglion cells, and glia). In OIR, FAD286 reduced neovascularization and neovascular tufts by 89% and 67%, respectively, and normalized the increase in vascular endothelial growth factor mRNA (1.74-fold) and protein (4.74-fold) and was as effective as valsartan and FAD286ϩvalsartan. In retina, aldosterone synthase mRNA was reduced with FAD286 but not valsartan. Aldosterone synthase was detected in microglia, ganglion cells, and glia, whereas mineralocorticoid receptor and 11␤-hydroxysteroid dehydrogenase 2 were present in all of the cell types studied. Given the location of aldosterone synthase in microglia and their contribution to retinal inflammation and neovascularization in OIR, the effects of FAD286 on microglial density were studied. The increase in microglial density (ionized calcium binding adaptor protein 1 immunolabeling) in OIR was reduced with all of the treatments. In OIR, FAD286 reduced the increase in mRNA for tumor necrosis factor-␣, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and monocyte chemoattractant molecule 1. These findings indicate that aldosterone inhibition may be a potential treatment for retinal neovascularization.

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AT₁ receptor inhibition prevents astrocyte degeneration and restores vascular growth in oxygen‐induced retinopathy

Cited by 81 publications

References 77 publications

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

Neurodegeneration: An early event of diabetic retinopathy

Neovascularization Is Attenuated With Aldosterone Synthase Inhibition in Rats With Retinopathy

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AT1 receptor inhibition prevents astrocyte degeneration and restores vascular growth in oxygen‐induced retinopathy

Cited by 81 publications

References 77 publications

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

Neurodegeneration: An early event of diabetic retinopathy

Neovascularization Is Attenuated With Aldosterone Synthase Inhibition in Rats With Retinopathy

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AT₁ receptor inhibition prevents astrocyte degeneration and restores vascular growth in oxygen‐induced retinopathy