Pathologic Roles of Receptor-Associated Prorenin System in Idiopathic Epiretinal Membrane

Dong, Yoko; Kanda, Atsuhiro; Noda, Kousuke; Saito, Wataru; Ishida, Susumu

doi:10.1038/srep44266

Cited by 11 publications

(17 citation statements)

References 30 publications

(67 reference statements)

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“…Our clinical sample data also revealed (P)RR involvement in retinal angiogenesis and systemic inflammation in patients with PDR, showing a close association of RAPS with the molecular mechanism of PDR [37][38][39]. Moreover, increasing evidence has suggested RAPS activation in various human eye disorders including age-related macular degeneration [40], idiopathic epiretinal membrane [41], noninfectious uveitis [42], and conjunctival lymphoma [43].…”

Section: Introductionsupporting

confidence: 63%

“…In the mouse model of diabetic retinopathy, leukocyte adhesion to the retinal vasculature was revealed to be governed independently by both AT1R and (P)RR [17,32]. Molecules induced via (P)RR downstream pathway and their cellular sources were reported to include monocyte chemotactic protein 1 in brain capillary endothelial cells [34], vascular endothelial growth factor A in macrophages [34] and retinal microvascular endothelial cells [37], transforming growth factor-β1 in retinal pigment epithelial cells [40], and fibroblast growth factor 2 in Müller glial cells [41]. (P)RR signaling would thus lead to various pathologic conditions such as inflammation, angiogenesis, and fibrosis, depending on different cellular reactions in diabetic retinopathy [37], age-related macular degeneration [40], and idiopathic epiretinal membrane [41].…”

Section: Discussionmentioning

confidence: 99%

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Receptor-Associated Prorenin System in the Trabecular Meshwork of Patients with Primary Open-Angle Glaucoma and Neovascular Glaucoma

Ishizuka¹,

Kanda²,

Shinmei³

et al. 2020

JCM

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The receptor-associated prorenin system (RAPS) is associated with several pathologic conditions, including diabetic retinopathy, age-related macular degeneration, and uveitis. Here, we show the involvement of RAPS in the trabecular meshwork (TM) from patients with primary open-angle glaucoma (POAG) and neovascular glaucoma (NVG) due to proliferative diabetic retinopathy. Anterior chamber (AC) levels of prorenin significantly increased in both POAG and NVG, as did those of angiotensin II in NVG alone, compared to cataract. In surgically excised TM tissues, (pro)renin receptor ((P)RR) and angiotensin II type 1 receptor (AT1R) co-localized with prorenin and angiotensinogen, respectively. In screening for various genes related to glaucoma, prorenin stimulation to human TM cells exclusively upregulated cell junction constituents connexin 43 and zona occludens 1, while downregulating an extracellular matrix-degrading enzyme tissue plasminogen activator, all of which were reversed by (P)RR blockade. In contrast, angiotensin II application upregulated a pro-angiogenic factor placental growth factor alone, which was abolished by AT1R blockade. Consistently, (P)RR and AT1R co-localized with these corresponding proteins in patient TM tissues. Oxidative stress, a known etiology for glaucoma, induced the expression of prorenin and angiotensinogen in human TM cells. These data suggest the contribution of RAPS to the molecular pathogenesis of POAG and NVG through TM tissue remodeling and AC angle angiogenesis.

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Section: Introductionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Receptor-Associated Prorenin System in the Trabecular Meshwork of Patients with Primary Open-Angle Glaucoma and Neovascular Glaucoma

Ishizuka¹,

Kanda²,

Shinmei³

et al. 2020

JCM

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“…Based on our findings, a blockade of (P)RR is theorized to inhibit the cascade of events crucial in various vascular abnormalities represented by inflammation and angiogenesis. Aliskiren, a direct renin inhibitor, competitively inhibited the renin enzymatic activity of both renin and activated prorenin through interaction with (P)RR in vitro ; however, RAS inhibitors including aliskiren have no efficacy of blocking (P)RR's own downstream signals.…”

Section: Development Of a Novel Single‐strand Rna Interference Therapmentioning

confidence: 70%

“…These results show that the close link between the RAPS components and CCL2/MCP‐1 levels would validate the pathogenic role of (P)RR that contributes to inflammation in human uveitis. Furthermore, we have shown that RAPS activation contributes to the molecular pathogenesis, including inflammation, angiogenesis and fibrosis, of other ocular disorders, such as conjunctival lymphoma and idiopathic epiretinal membrane.…”

Section: (Pro)renin Receptor In Uveitismentioning

confidence: 99%

(Pro)renin receptor: Involvement in diabetic retinopathy and development of molecular targeted therapy

Kanda

Ishida

2018

J of Diabetes Invest

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The renin-angiotensin system (RAS), a crucial regulator of systemic blood pressure (circulatory RAS), plays distinct roles in pathological angiogenesis and inflammation in various organs (tissue RAS), such as diabetic microvascular complications. Using ocular clinical samples and animal disease models, we elucidated molecular mechanisms in which tissue RAS excites the expression of vascular endothelial growth factor (VEGF)-A responsible for retinal inflammation and angiogenesis, the two major pathological events in diabetic retinopathy (DR). Furthermore, we showed the involvement of (pro)renin receptor [(P)RR] in retinal RAS activation and its concurrent intracellular signal transduction (e.g., extracellular signal-regulated kinase); namely, the (P)RR-induced dual pathogenic bioactivity referred to as the receptor-associated prorenin system. Indeed, neovascular endothelial cells in the fibrovascular tissue collected from eyes with proliferative DR were immunoreactive for the receptor-associated prorenin system components including prorenin, (P)RR, phosphorylated extracellular signal-regulated kinase and VEGF-A. Protein levels of soluble (P)RR increased with its positive correlations with prorenin, renin enzymatic activity and VEGF in the vitreous of proliferative DR eyes, suggesting a close link between (P)RR and VEGF-A-driven angiogenic activity. Furthermore, we revealed an unsuspected, PAPS-independent role of (P)RR in glucose-induced oxidative stress. Recently, we developed an innovative single-strand ribonucleic acid interference molecule selectively targeting human and mouse (P)RR, and confirmed its efficacy in suppressing diabetes-induced retinal inflammation in mice. Our data using clinical samples and animal models suggested the significant implication of (P)RR in the pathogenesis of DR, and the potential usefulness of the ribonucleic acid interference molecule as a therapeutic agent to attenuate ocular inflammation and angiogenesis.

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“…To investigate which pro-fibrotic cytokine can induce mesenchymal (EMT-like) changes in human Müller glial cells, we stimulated MIO-M1 cells with various cytokines and growth factors known for their fibrogenic activity and/or their protein expression in the iERM tissue 12,16,17 , and analyzed mRNA expression levels of several EMT-related molecular markers by real-time quantitative PCR. Smooth muscle protein (SM)22, also known as transgelin encoded by the TAGLN gene, is an actin-binding cytoskeletal protein recently utilized as another marker for myofibroblasts and mesenchymal cells, on top of conventionally used α-SMA 18–20 .…”

Section: Resultsmentioning

confidence: 99%

TGF-β-SNAIL axis induces Müller glial-mesenchymal transition in the pathogenesis of idiopathic epiretinal membrane

Kanda

Noda

Hirose

et al. 2019

Sci Rep

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The epithelial-mesenchymal transition (EMT) is a key process in fibrogenic diseases where transdifferentiated myofibroblasts produce excessive amounts of extracellular matrix, resulting in organ dysfunction. Idiopathic epiretinal membrane (iERM) is a vision-threatening disorder characterized by fibrocellular proliferation and contraction on the central retina. Müller glial cells, which regulate retinal physiology and structure, are the major cellular components in the iERM tissue; however, the pathological role of this cell type remains incompletely understood. Here we revealed the involvement of Müller glial-mesenchymal transition (GMT), as an alternative to EMT, in the pathogenesis of iERM lacking epithelial contribution in nature. Of various pro-fibrotic cytokines, transforming growth factor (TGF)-β1 stimulation to human Müller glial cells exclusively increased mRNA and protein levels of several EMT-related molecular markers, together with the transcription factor SNAIL but not SLUG or TWIST. TGF-β1-stimulated Müller cells also exhibited EMT-related cell motility, while reducing the expression of glutamine synthetase (GS), a Müller glial marker. Notably, all of these TGF-β-induced EMT features were reversed by SNAI1 knockdown in Müller cells. iERM patient specimens demonstrated co-immunolocalization of SNAIL with TGF-β1, GS, and smooth muscle protein 22. Our data implicated a critical role of the TGF-β-SNAIL axis in Müller GMT to promote iERM formation.

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Pathologic Roles of Receptor-Associated Prorenin System in Idiopathic Epiretinal Membrane

Cited by 11 publications

References 30 publications

Receptor-Associated Prorenin System in the Trabecular Meshwork of Patients with Primary Open-Angle Glaucoma and Neovascular Glaucoma

Receptor-Associated Prorenin System in the Trabecular Meshwork of Patients with Primary Open-Angle Glaucoma and Neovascular Glaucoma

(Pro)renin receptor: Involvement in diabetic retinopathy and development of molecular targeted therapy

TGF-β-SNAIL axis induces Müller glial-mesenchymal transition in the pathogenesis of idiopathic epiretinal membrane

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