1. Adiponectin-induced activation of ERK1/2 drives fibrosis in retinal pigment epithelial cells.
- Author
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Palanisamy K, Karpagavalli M, Nareshkumar RN, Ramasubramanyan S, Angayarkanni N, Raman R, and Chidambaram S
- Subjects
- Humans, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Tight Junctions metabolism, Cell Movement genetics, Diabetic Retinopathy metabolism, Diabetic Retinopathy pathology, Diabetic Retinopathy etiology, Cell Line, Gene Expression genetics, Cell Proliferation genetics, Cell Transdifferentiation, Epithelial Cells metabolism, Cells, Cultured, Matrix Metalloproteinase 2 metabolism, Matrix Metalloproteinase 2 genetics, Tight Junction Proteins metabolism, Epithelial-Mesenchymal Transition genetics, Adiponectin metabolism, Adiponectin physiology, Retinal Pigment Epithelium metabolism, Retinal Pigment Epithelium pathology, Fibrosis, MAP Kinase Signaling System physiology, MAP Kinase Signaling System genetics
- Abstract
Adiponectin (APN), a vasoactive cytokine produced by adipocytes, has emerged as a critical player in retinal diseases. Renowned for its antioxidant, anti-angiogenic, and anti-inflammatory properties, APN levels are closely linked to metabolic disorders, such as insulin resistance, obesity, and diabetic retinopathy (DR). Our previous work demonstrated that APN is similar in efficiency as Avastin in limiting neovascularization in retinal endothelial cells. In this study, we analyzed the effect of APN on retinal epithelial cells to understand its potential impact on eye-related pathologies. Overexpression of APN in ARPE-19 cells predominantly yielded the MMW-APN form, accompanied by increased expression of pro-fibrotic markers and decreased levels of tight junction (TJ) proteins, ZO-1, and Occludin. Further, confocal imaging revealed impaired TJ assembly and the integrity of TJ was also compromised as evidenced by the higher paracellular permeability and lower TEER. Besides, rAPN treatment in ARPE-19 cells as well triggered increased expression of pro-fibrotic markers, pro-MMP2, and enhanced cell migration and proliferation. Mechanistically, these pro-fibrotic effects were mediated by APN-induced phosphorylation of ERK1/2, causing RPE cell transdifferentiation. Furthermore, we identified that MMW-APN was the most prevalent form detected in the vitreous humor of proliferative diabetic retinopathy (PDR) patients, emphasizing the clinical relevance of our findings. Overall, our data suggest that APN, particularly its MMW form, induces epithelial-mesenchymal transition (EMT) and fibrosis in RPE cells, potentially driving the angio-fibrotic shift observed in PDR via ERK1/2 activation., (© 2024. The Author(s) under exclusive licence to Japan Human Cell Society.)
- Published
- 2024
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