Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma
Gareth R. Howell, … , Richard T. Libby, Simon W.M. John
Gareth R. Howell, … , Richard T. Libby, Simon W.M. John
Published March 7, 2011
Citation Information: J Clin Invest. 2011;121(4):1429-1444. https://doi.org/10.1172/JCI44646.
View: Text | PDF
Research Article Ophthalmology Article has an altmetric score of 6

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

  • Text
  • PDF
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.

Authors

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

×

Figure 1

Early stages of glaucoma identified by hierarchical clustering.

Options: View larger image (or click on image) Download as PowerPoint
Early stages of glaucoma identified by hierarchical clustering.
(A) Pair...
(A) Pairwise comparisons for eyes grouped by conventional morphological assessment of optic nerve damage (Dataset 1). The numbers of DE genes compared with controls are shown for both the ONH and retina. NOE eyes had no detectable glaucoma; MOD and SEV eyes had readily detectable damage and significant axon loss (Supplemental Figure 1). A total of 40 DBA/2J eyes were compared with the 10 controls. (B) A glaucoma-relevant probe set (see Methods and Supplemental Figure 1) was used to cluster the same eyes into molecular stages based on expression profiles of ONH samples. The expression data for all 50 eyes are shown. Five molecularly defined stages containing at least 4 eyes were identified (ONH stages 1–5). The optic nerve damage level is indicated on the left for control, NOE, and SEV eyes. All unlabeled eyes had MOD glaucoma. Black horizontal lines indicate borders between stages. The red line indicates the cutoff level for inclusion in a stage. Raw normalized intensity values are represented as green to black to red. For each probe set, green represents the lower normalized intensity values across all eyes and red the higher intensity values. All normalized intensity values for each probe set are available in Geo DataSets (GSE26299). (C) Pairwise comparisons for these molecular stages (Dataset 2). Stage 3 contains 3 eyes with no detectable glaucoma and 3 eyes with detectable glaucoma. The numbers of DE genes for the ONH and retina for each stage are shown.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Referenced in 4 patents
Referenced in 2 Wikipedia pages
177 readers on Mendeley
See more details