Dataset Information

Involvement of Muller Glial Autoinduction of TGF-? in Diabetic Fibrovascular Proliferation Via Glial-Mesenchymal Transition.

ABSTRACT:

Purpose

Müller glial-mesenchymal transition (GMT) is reported as the fibrogenic mechanism promoted by TGF-?-SNAIL axis in Müller cells transdifferentiated into myofibroblasts. Here we show the multifaceted involvement of TGF-? in diabetic fibrovascular proliferation via Müller GMT and VEGF-A production.

Methods

Surgically excised fibrovascular tissues from the eyes of patients with proliferative diabetic retinopathy were processed for immunofluorescence analyses of TGF-? downstream molecules. Human Müller glial cells were used to evaluate changes in gene and protein expression with real-time quantitative PCR and ELISA, respectively. Immunoblot analyses were performed to detect TGF-? signal activation.

Results

Müller glial cells in patient fibrovascular tissues were immunopositive for GMT-related molecular markers, including SNAIL and smooth muscle protein 22, together with colocalization of VEGF-A and TGF-? receptors. In vitro administration of TGF-?1/2 upregulated TGFB1 and TGFB2, both of which were suppressed by inhibitors for nuclear factor-?B, glycogen synthase kinase-3, and p38 mitogen-activated protein kinase. Of the various profibrotic cytokines, TGF-?1/2 application exclusively induced Müller glial VEGFA mRNA expression, which was decreased by pretreatment with small interfering RNA for SMAD2 and inhibitors for p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase. Supporting these findings, TGF-?1/2 stimulation to Müller cells increased the phosphorylation of these intracellular signaling molecules, all of which were also activated in Müller glial cells in patient fibrovascular tissues.

Conclusions

This study underscored the significance of Müller glial autoinduction of TGF-? as a pathogenic cue to facilitate diabetic fibrovascular proliferation via TGF-?-driven GMT and VEGF-A-driven angiogenesis.

SUBMITTER: Wu D

PROVIDER: S-EPMC7774059 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

Involvement of Müller Glial Autoinduction of TGF-β in Diabetic Fibrovascular Proliferation Via Glial-Mesenchymal Transition.

Wu Di D Kanda Atsuhiro A Liu Ye Y Noda Kousuke K Murata Miyuki M Ishida Susumu S

Investigative ophthalmology & visual science 20201201 14

<h4>Purpose</h4>Müller glial-mesenchymal transition (GMT) is reported as the fibrogenic mechanism promoted by TGF-β-SNAIL axis in Müller cells transdifferentiated into myofibroblasts. Here we show the multifaceted involvement of TGF-β in diabetic fibrovascular proliferation via Müller GMT and VEGF-A production.<h4>Methods</h4>Surgically excised fibrovascular tissues from the eyes of patients with proliferative diabetic retinopathy were processed for immunofluorescence analyses of TGF-β downstrea ...[more]

PMID: 33369638

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