JNK inhibition reduces apoptosis and neovascularization in a murine model of age-related macular degeneration
Open accessAbstract
Age-related macular degeneration (AMD) is the leading cause of registered blindness among the elderly and affects over 30 million people worldwide. It is well established that oxidative stress, inflammation, and apoptosis play critical roles in pathogenesis of AMD. In advanced wet AMD, although, most of the severe vision loss is due to bleeding and exudation of choroidal neovascularization (CNV), and it is well known that vascular endothelial growth factor (VEGF) plays a pivotal role in the growth of the abnormal blood vessels. VEGF suppression therapy improves visual acuity in AMD patients. However, there are unresolved issues, including safety and cost. Here we show that mice lacking c-Jun N-terminal kinase 1 (JNK1) exhibit decreased inflammation, reduced CNV, lower levels of choroidal VEGF, and impaired choroidal macrophage recruitment in a murine model of wet AMD (laser-induced CNV). Interestingly, we also detected a substantial reduction in choroidal apoptosis of JNK1-deficient mice. Intravitreal injection of a pan-caspase inhibitor reduced neovascularization in the laser-induced CNV model, suggesting that apoptosis plays a role in laser-induced pathological angiogenesis. Intravitreal injection of a specific JNK inhibitor decreased choroidal VEGF expression and reduced pathological CNV. These results suggest that JNK1 plays a key role in linking oxidative stress, inflammation, macrophage recruitment apoptosis, and VEGF production in wet AMD and pharmacological JNK inhibition offers a unique and alternative avenue for prevention and treatment of AMD.
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Activation of MAPK components-ERK, JNK, and p38 MAPK-has been observed in human RPE cultures and animal models of AMD.
“Notably, activation of MAPK components-such as extracellular signal-regulated kinase (ERK), cJun N-terminal kinase (JNK), and p38 MAPK-has been observed in human RPE cultures and animal models of AMD 18,19”
From rAAV-mediated Multi-miRNA Delivery Targeting MAPK Pathway Suppresses Laser-induced Choroidal Neovascularization in Mice (2026) · cites this paper as [18]
In “Reduction of CNV and Inflammation in Jnk1−/− Mice” (page unavailable), the paper reports increased c-Jun phosphorylation as evidence of JNK activation in a mouse model of wet AMD. It does not report activation of all three MAPK components in human RPE cultures and animal models; ERK appears in a cited reference, and the retrieved passages do not address p38 MAPK. (LLM, conf=0.89)
Experimental — accuracy not yet measuredIn a mouse model of laser-induced choroidal neovascularization, JNK inhibition led to a decrease in apoptosis, decrease in VEGF expression, and a reduction in neovascularization.
“while in yet another mouse model of laser-induced choroidal neovascularization, JNK inhibition led to a decrease in apoptosis, decrease in VEGF expression, and a reduction in neovascularization [ 36 ].”
From MAPK Pathways in Ocular Pathophysiology: Potential Therapeutic Drugs and Challenges (2023) · cites this paper as [36]
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- Authors
- Du, H., Sun, X., Guma, M., Luo, J., Ouyang, H., Zhang, X., Zeng, J., Quach, J., Nguyen, D. H., Shaw, P. X., Karin, M., & Zhang, K.
- Affiliations
- Sichuan University (CN)
- University of California San Diego (US)
- Laboratory of Gene Regulation and Signal Transduction, and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-01-22
- Volume
- 110
- Issue
- 6
- Pages
- 2377-2382
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3568328
- OpenAlex
- W2043188804
- Cited by
- 74
- References
- 30
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 6 · 2023: 10 · 2022: 1 · 2021: 3 · 2020: 7 · 2019: 6 · 2018: 7 · 2017: 3 · 2016: 10 · 2015: 3 · 2014: 5 · 2013: 4
- FWCI
- 7.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Burroughs Wellcome Fund
- Arthritis Foundation
- King Abdulaziz City for Science and Technology
- National Institutes of Health (ES010337)
- University of California, San Diego
- National Key Research and Development Program of China (2011CB510200)
- National Eye Institute (EY019270, R01EY019270, R01EY018660, R01EY014428, EY018660, EY014428, R01EY021374, EY021374)
- National Institute of Environmental Health Sciences (P42ES010337, ES-006376, ES 010337, ES00451, R01ES006376)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- age-related macular degeneration, neovascular age-related macular degeneration, choroidal neovascularization, JNK1, apoptosis, vascular endothelial growth factor, oxidative stress, inflammation, pathological angiogenesis, pan-caspase inhibitor, laser-induced CNV
- MeSH terms
- Amino Acid Chloromethyl Ketones, Animals, Disease Models, Animal, Humans, Macrophages, Macular Degeneration, Mice, Inbred C57BL, Cysteine Proteinase Inhibitors, Cytokines, Apoptosis, Mice, Knockout, Oxidative Stress, Inflammation Mediators, Choroidal Neovascularization, Vascular Endothelial Growth Factor A, Mitogen-Activated Protein Kinase 8, Mice
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