Inhibiting autophagy by miR-19a-3p/PTEN regulation protected retinal pigment epithelial cells from hyperglycemic damage |
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| Institution: | 1. Department of Pathophysiology, Medical College, Nanchang University, Nanchang 330006, China;2. Second Clinical Medical College, Nanchang University, Nanchang 330006, China;3. First Clinical Medical College, Nanchang University, Nanchang 330006, China;4. Key Laboratory of Functional and Clinical Translational Medicine, Xiamen Medical College, Fujian province university, Xiamen 361023, China;5. Department of Burn, The First Affiliated Hospital, Nanchang University, Nanchang 330066, China;1. Department of Plastic Surgery, the first affiliated hospital of Jinan University, No. 613, Huangpu Avenue West, Tianhe District, Guangzhou 510630, China;2. Medical college of Jianghan University, No. 8, Sanjiaohu Road, Wuhan Economic and Technological Development Zone, Wuhan 430014, China;3. Department of Burns and Plastic, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, China;4. Innovative Technology Research Institute of Plastic Surgery, Guangzhou 510630, People’s Republic of China;5. Key Laboratory of Regenerative Medicine, Ministry of Education, Guangzhou 510632, People’s Republic of China;1. Department of Medical Cosmetology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China;2. Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China;3. Department of Plastic Surgery, China-Japan Friendship Hospital, Beijing 100029, China;1. Department of Proteomics, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 12820 Prague 2, Czech Republic;1. Cancer Research Program-12, Rajiv Gandhi Centre for Biotechnology (DBT-RGCB), Thycaud. P.O. Thiruvananthapuram-14, Kerala, India;2. Manipal Academy of Higher Education, Tiger Circle Road, Madhav Nagar, Manipal, Karnataka 576104, India;3. Neuro Stem Cell Biology Laboratory, Neurobiology Division, Rajiv Gandhi Centre for Biotechnology (DBT-RGCB), Thiruvananthapuram, Kerala 695 014, India;4. Regional Centre for Biotechnology (DBT-RCB), Faridabad, Haryana 121001, India |
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| Abstract: | ObjectiveThe 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.MethodsAn 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.ResultsAutophagy 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.ConclusionsOur 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. |
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