Cited by 479Glaucoma and retinal disordersRetinal Diseases and TreatmentsRetinal Imaging and Analysis

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Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma

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Howell, Gareth R., Macalinao, Danilo G., Sousa, Gregory L., Walden, Michael, Soto, Ileana, Kneeland, Stephen C., Barbay, Jessica M., King, Benjamin L., Marchant, Jeffrey K., Hibbs, Matthew, Stevens, Beth, Barres, Ben A., Clark, Abbot F., Libby, Richard T., John, Simon W.M.·2011·Journal of Clinical Investigation

DOI 10.1172/jci44646PMC PMC3069778

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Abstract

Glaucoma is one of the most common neurodegenerative diseases. Despite this, the earliest stages of this complex disease are still unclear. This study was specifically designed to identify early stages of glaucoma in DBA/2J mice. To do this, we used genome-wide expression profiling of optic nerve head and retina and a series of computational methods. Eyes with no detectable glaucoma by conventional assays were grouped into molecularly defined stages of disease using unbiased hierarchical clustering. These stages represent a temporally ordered sequence of glaucoma states. We then determined networks and biological processes that were altered at these early stages. Early-stage expression changes included upregulation of both the complement cascade and the endothelin system, and so we tested the therapeutic value of separately inhibiting them. Mice with a mutation in complement component 1a (C1qa) were protected from glaucoma. Similarly, inhibition of the endothelin system with bosentan, an endothelin receptor antagonist, was strongly protective against glaucomatous damage. Since endothelin 2 is potently vasoconstrictive and was produced by microglia/macrophages, our data provide what we believe to be a novel link between these cell types and vascular dysfunction in glaucoma. Targeting early molecular events, such as complement and endothelin induction, may provide effective new treatments for human glaucoma.

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Siddiqui, A. M. (2013) · MacSphere (McMaster University) · doi:10.71548/21084

Authors: Howell, G. R., Macalinao, D. G., Sousa, G. L., Walden, M., Soto, I., Kneeland, S. C., Barbay, J. M., King, B. L., Marchant, J. K., Hibbs, M., Stevens, B., Barres, B. A., Clark, A. F., Libby, R. T., & John, S. W. M.
Affiliations: Howard Hughes Medical Institute (US)
Jackson Laboratory (US)
Mount Desert Island Biological Laboratory (US)
Tufts University (US)
Harvard University (US)
Stanford University (US)
University of North Texas Health Science Center (US)
University of Rochester (US)
Corresponding author: John, Simon W.M.
ORCID: Howell, Gareth R.
Macalinao, Danilo G.
Sousa, Gregory L.
Soto, Ileana
King, Benjamin L.
Marchant, Jeffrey K.
Hibbs, Matthew
Stevens, Beth
Barres, Ben A.
Clark, Abbot F.
Libby, Richard T.
John, Simon W.M.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2011-04-01
Volume: 121
Issue: 4
Pages: 1429-1444
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci44646
PMC: PMC3069778
OpenAlex: W1983740408
Cited by: 473
References: 77
Citations by year: 2026: 25 · 2025: 28 · 2024: 20 · 2023: 46 · 2022: 43 · 2021: 34 · 2020: 39 · 2019: 26 · 2018: 24 · 2017: 33 · 2016: 29 · 2015: 35 · 2014: 24 · 2013: 28 · 2012: 28
FWCI: 26.40
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
Funders: Howard Hughes Medical Institute
American Health Assistance Foundation
Research to Prevent Blindness
National Institutes of Health (NIH T32, EY011721)
National Eye Institute (EY018606, R29EY011721, R01EY018606, R01EY011721, EY011721, F32EY014515)
National Institute of Neurological Disorders and Stroke (T32 NS51112-05, T32NS051112)
Topics: Health Sciences › Medicine › Ophthalmology › Glaucoma and retinal disorders
Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinal Imaging and Analysis
Keywords: glaucoma, early-stage disease, complement system, endothelin system, endothelin receptor antagonism, bosentan, C1QA, optic nerve head, retina, microglia/macrophages, vascular dysfunction, disease progression, therapeutic target, DBA/2J mice
MeSH terms: Bosentan, Animals, Disease Models, Animal, Female, Glaucoma, Humans, Mice, Inbred DBA, Mice, Mutant Strains, Optic Nerve, Retina, Sulfonamides, Signal Transduction, Up-Regulation, Complement C1q, Cluster Analysis, Endothelin-2, Gene Expression Profiling, Mice, Endothelin Receptor Antagonists

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Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma

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