Angiotensin II related glial cell activation and necroptosis of retinal ganglion cells after systemic hypotension in glaucoma

Jeon, Soo Ji; Huh, Jungbin; Jeong, Eojin; Park, Chan Kee

doi:10.1038/s41419-022-04762-4

Cited by 13 publications

(16 citation statements)

References 41 publications

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“…In the model of proliferative Diabetic et al, 2000;Shi et al, 2010;Hatzopoulos et al, 2014). And up-regulating the expression of retinal Ang II promotes the expression of TNF-α secreted by the activated glial cells which contributes to the death of RGC (Jeon et al, 2022). Activated microglia secrete Agt and Ang II resulting in angiogenesis during tissue injury or disease (Mills et al, 2021).…”

Section: Potential Targets Of Microglia In Retinopathymentioning

confidence: 99%

Microglia: The breakthrough to treat neovascularization and repair blood-retinal barrier in retinopathy

Feng

Qin

et al. 2023

Front. Mol. Neurosci.

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Microglia are the primary resident retinal macrophages that monitor neuronal activity in real-time and facilitate angiogenesis during retinal development. In certain retinal diseases, the activated microglia promote retinal angiogenesis in hypoxia stress through neurovascular coupling and guide neovascularization to avascular areas (e.g., the outer nuclear layer and macula lutea). Furthermore, continuously activated microglia secrete inflammatory factors and expedite the loss of the blood-retinal barrier which causes irreversible damage to the secondary death of neurons. In this review, we support microglia can be a potential cellular therapeutic target in retinopathy. We briefly describe the relevance of microglia to the retinal vasculature and blood-retinal barrier. Then we discuss the signaling pathway related to how microglia move to their destinations and regulate vascular regeneration. We summarize the properties of microglia in different retinal disease models and propose that reducing the number of pro-inflammatory microglial death and conversing microglial phenotypes from pro-inflammatory to anti-inflammatory are feasible for treating retinal neovascularization and the damaged blood-retinal barrier (BRB). Finally, we suppose that the unique properties of microglia may aid in the vascularization of retinal organoids.

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Section: Potential Targets Of Microglia In Retinopathymentioning

confidence: 99%

Microglia: The breakthrough to treat neovascularization and repair blood-retinal barrier in retinopathy

Feng

Qin

et al. 2023

Front. Mol. Neurosci.

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“…We previously con rmed that low and unstable BP upregulates the AngII level in the serum and retinal tissues of this systemic hypotensive animal model and that this was related to the death of RGCs by necroptosis. 20 As AngII has a role in tissue brosis of various organs, AngII could have a role in scleral brosis. Increased AT-1R and AT-2R levels were detected in the sclera after inducing systemic hypotension in the animal model.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II-related activation of scleral fibroblasts and the role of retinal ganglion cell death in glaucoma

Kim

Shin

et al. 2023

Preprint

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We identify the angiotensin II (AngII)-associated changes in the extracellular matrix (ECM), and the biomechanical properties of the sclera after systemic hypotension. Systemic hypotension was induced by administering oral hydrochlorothiazide. AngII receptor levels and ECM components in the sclera and biomechanical properties were evaluated by stress–strain relationship after systemic hypotension. The effect of inhibiting the AngII receptor with losartan was determined in the systemic hypotensive animal model and the cultured scleral fibroblasts from this model. The effect of losartan on retinal ganglion cell (RGC) death was evaluated in the retina. Both AngII receptor type I (AT-1R) and type II (AT-2R) increased in the sclera after systemic hypotension. Proteins related to the activation of fibroblasts (transforming growth factor [TGF]-β1 and TGF-β2) indicated that transformation to myofibroblasts (αSMA), and the major ECM protein (collagen type I) increased in the sclera after systemic hypotension. These changes were associated with stiffening of the sclera in the biomechanical analysis. Administering losartan in the Tenon’s tissue significantly decreased the expression of AT-1R, αSMA, TGF-β, and collagen type I in the cultured scleral fibroblasts and the sclera of systemic hypotensive rats. The sclera became less stiff after the losartan treatment. A significant increase in the number of RGCs and decrease in glial cell activation was found in the retina after the losartan treatment. These findings suggest that AngII has a role in scleral fibrosis after systemic hypotension and that inhibiting AngII could modulate the tissue properties of the sclera resulting in the protection of RGCs.

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“…In patients with NTG and with central scotoma, vascular instability may contribute to glial cell activation promoting release of TNF-α. Recently, we investigated how blood pressure instability could contribute to retinal ganglion cell damage in glaucoma animal models [ 29 ]. Glial cell activation and TNF-α mediated cell death was a contributing mechanism in this glaucoma model.…”

Section: Discussionmentioning

confidence: 99%

Factors Associated with Elevated Tumor Necrosis Factor-α in Aqueous Humor of Patients with Open-Angle Glaucoma

Jung

Ohn

Shin

et al. 2022

JCM

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Tumor necrosis factor-alpha (TNF-α) is an important modulator of neuroinflammation, secreted from activated glial cells in response to intraocular stress. The purpose of this study was to investigate the clinical factors associated with elevated TNF-α and its level in aqueous humor of patients with open-angle glaucoma (OAG). Aqueous humor was collected from 73 OAG eyes, and TNF-α level was analyzed using the singleplex bead immunoassay method. Patients were divided into TNF-α-positive and TNF-α-negative groups according to the TNF-α level of 10 pg/mL, and baseline clinical characteristics were compared. The TNF-α-positive group showed higher baseline IOP, greater IOP fluctuation, and higher systolic blood pressure than the TNF-α-negative group (p = 0.007, p < 0.001, and p = 0.009, respectively). In the multivariate logistic regression analysis, IOP fluctuation (p = 0.037) and systolic blood pressure (p = 0.016) were all independently associated with positive TNF-α level. In normal-tension glaucoma (NTG) patients, presence of central scotoma (p = 0.029) was significantly associated with positive TNF-α level. In conclusion, positive TNF-α level in OAG patients was associated with greater IOP fluctuation and higher systolic blood pressure. In NTG patients, positive TNF-α level was associated with the presence of central scotoma. IOP factors and vascular factors, including blood pressure and presence of central scotoma, may indicate glaucoma pathogenesis related to TNF-α elevation in OAG patients.

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Angiotensin II related glial cell activation and necroptosis of retinal ganglion cells after systemic hypotension in glaucoma

Cited by 13 publications

References 41 publications

Microglia: The breakthrough to treat neovascularization and repair blood-retinal barrier in retinopathy

Microglia: The breakthrough to treat neovascularization and repair blood-retinal barrier in retinopathy

Angiotensin II-related activation of scleral fibroblasts and the role of retinal ganglion cell death in glaucoma

Factors Associated with Elevated Tumor Necrosis Factor-α in Aqueous Humor of Patients with Open-Angle Glaucoma

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