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Updated: Feb 18, 2026
Real-Time Analysis of Bioenergetics in Primary Human Retinal Pigment Epithelial Cells Using High-Resolution Respirometry
Published on: February 3, 2023
TAK1 inhibition accelerates cellular senescence of retinal pigment epithelial cells
Zeev Dvashi1, Yaron Green1, Ayala Pollack1
1Kaplan Medical Center, affiliated with Hadassah-Hebrew University of Jerusalem, Rehovot, Israel.
Purpose:
Oxidative stress and cellular senescence are known to contribute to the development of AMD; however, the mechanism is not fully understood. This study investigated the role of TGF-β-activated kinase 1 (TAK1) in the senescence of RPE cells as a model for the development of dry AMD.
Methods:
Cultured human RPE cells were treated with the TAK1 inhibitor 5Z-7-oxozeaenol for 1 hour, and then treated with 200 μM hydrogen peroxide for 1 hour. Human RPE cells that were not pretreated with TAK1 inhibitor for 1 hour served as controls. Senescence-associated β-galactosidase (SA-β-gal) activity was detected by histochemistry, and p53 expression by immunoblotting. Cell-cycle and apoptosis rate in RPE cells were determined by flow cytometry.
Results:
The TAK1 expression in human RPE cells was high and was altered on oxidative stress. Transforming growth factor-β-activated kinase 1 inhibition led to reduction in cell proliferation, cell-cycle arrest at G0/G1, and increased SA-β-gal expression, all known to be features of cell senescence. Exposure of cells to oxidative stress combined with inhibition of TAK1 activity decreased the expression of apoptotic proteins, such as p53, and promoted cellular senescence. Aberrant TAK1 activity in RPE cells triggered their secretion of factors that induced hypertrophy and fibrotic changes in neighboring cells.
Conclusions:
The in vitro evidence indicated a role for TAK1 in the onset of senescence in RPE cells. The data shown hereby demonstrated that TAK1 activity is essential for maintaining normal function of RPE cells. Elucidation of its role in mechanisms underlying RPE cellular senescence induction may potentiate development of powerful tools for halting the development of dry AMD.
Insights
Transforming growth factor-β-activated kinase 1 (TAK1) inhibition promotes RPE cell senescence, a key factor in dry age-related macular degeneration (AMD). This suggests TAK1 plays a crucial role in RPE cell function and offers potential therapeutic targets for AMD.
Area of Science:
- Ophthalmology
- Cell Biology
- Molecular Biology
Background:
- Oxidative stress and cellular senescence are implicated in Age-related Macular Degeneration (AMD) pathogenesis.
- The precise mechanisms linking these factors to AMD, particularly dry AMD, remain incompletely understood.
- Retinal Pigment Epithelial (RPE) cells are critical for retinal health and are susceptible to senescence.
Purpose of the Study:
- To investigate the role of Transforming Growth Factor-β-Activated Kinase 1 (TAK1) in the senescence of RPE cells.
- To model the contribution of RPE cell senescence to the development of dry AMD.
- To explore TAK1's mechanism in oxidative stress-induced RPE cell senescence.
Main Methods:
- Human RPE cells were treated with a TAK1 inhibitor (5Z-7-oxozeaenol) followed by hydrogen peroxide exposure.
- Senescence was assessed by detecting senescence-associated β-galactosidase (SA-β-gal) activity.
- Cell-cycle progression and apoptosis rates were analyzed using flow cytometry, and p53 expression was evaluated via immunoblotting.
Main Results:
- TAK1 expression was found to be high in RPE cells and altered by oxidative stress.
- TAK1 inhibition reduced cell proliferation, induced G0/G1 cell-cycle arrest, and increased SA-β-gal expression, indicating senescence.
- Combined TAK1 inhibition and oxidative stress decreased apoptotic protein expression (e.g., p53) and promoted RPE cell senescence, with aberrant TAK1 activity inducing fibrotic changes in neighboring cells.
Conclusions:
- In vitro findings suggest TAK1 is involved in initiating RPE cell senescence.
- TAK1 activity is essential for maintaining the normal function of RPE cells.
- Understanding TAK1's role in RPE senescence could lead to novel therapeutic strategies for halting dry AMD progression.
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