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Published on: January 12, 2024
Inhibiting autophagy by miR-19a-3p/PTEN regulation protected retinal pigment epithelial cells from hyperglycemic
Qiaoyun Gong1, Dawei Luo1, Haiyan Wang1
1Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China; National Clinical Research Center for Eye Diseases, Shanghai, China; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China; Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Disease, Shanghai, China.
Objective:
The catabolic process of autophagy is arousing the attention of researchers studying diabetic retinopathy (DR), but the role and molecular mechanism of autophagy in DR are still unclear.
Methods:
An in vivo diabetic rat model and in vitro hyperglycemic-exposed retinal pigment epithelium (RPE) cell cultures were established to mimic early DR. Transmission electron microscopy and mRFP-GFP-LC3 adenovirus transfection were applied for autophagic flux analysis. MicroRNA (miR)-19a-3p, members of the phosphate and tensin homolog (PTEN)/Akt/mammalian target of rapamycin (mTOR) pathway, and the autophagy-related proteins light chain (LC)3II/I and p62 were detected. Annexin V, transwell, Cell Counting Kit-8, fluorescein isothiocyanate-dextran monolayer permeability assay, and transepithelial electrical resistance were performed to evaluate the effects of regulating autophagy on RPE cells under the DR condition.
Results:
Autophagy was aberrantly activated in DR as evidenced by autophagosome accumulation. Further mechanistic experiments revealed that DR induced PTEN expression, thus inhibiting Akt/mTOR phosphorylation and stimulating aberrant autophagy and apoptosis. Notably, these events could be reversed by miR-19a-3p directly targeting PTEN. Downregulation of autophagy by miR-19a-3p overexpression, PTEN knockdown, or 3-methyladenine (3-MA) treatment inhibited autophagosome formation and thus effectively ameliorated hyperglycemia-induced RPE cell apoptosis, increased migration, inhibited viability, and enhanced monolayer permeability under the DR condition.
Conclusions:
Our findings suggest that upregulation of miR-19a-3p inhibits aberrant autophagy by directly targeting PTEN, thus protecting RPE cells against DR damage. miR-19a-3p may represent a novel therapeutic target for inducing protective autophagy in early DR.
Insights
Diabetic retinopathy (DR) involves aberrant autophagy. Upregulating microRNA (miR)-19a-3p inhibits this process by targeting PTEN, protecting retinal cells and offering a potential therapy for DR.
Area of Science:
- Ophthalmology
- Cell Biology
- Molecular Biology
Background:
- Diabetic retinopathy (DR) is a complication of diabetes affecting the retina.
- The role of autophagy, a cellular degradation process, in DR pathogenesis is not fully understood.
- Understanding the molecular mechanisms of autophagy in DR is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role and molecular mechanism of autophagy in diabetic retinopathy (DR).
- To explore the potential of microRNA (miR)-19a-3p as a therapeutic target for DR.
Main Methods:
- Established in vivo diabetic rat and in vitro hyperglycemic retinal pigment epithelium (RPE) cell models.
- Analyzed autophagic flux using transmission electron microscopy and mRFP-GFP-LC3 adenovirus.
- Quantified miR-19a-3p, PTEN/Akt/mTOR pathway components, and autophagy-related proteins (LC3II/I, p62).
- Assessed RPE cell apoptosis, migration, viability, and permeability using various assays.
Main Results:
- Autophagy was aberrantly activated with autophagosome accumulation in DR models.
- DR induced PTEN expression, inhibiting Akt/mTOR and promoting autophagy and apoptosis.
- miR-19a-3p directly targeted PTEN, reversing these DR-associated changes.
- Downregulating autophagy via miR-19a-3p, PTEN knockdown, or 3-MA treatment protected RPE cells.
Conclusions:
- Upregulation of miR-19a-3p inhibits aberrant autophagy by targeting PTEN, protecting RPE cells from DR damage.
- miR-19a-3p shows promise as a novel therapeutic target for inducing protective autophagy in early DR.
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