Global metabolomics reveals metabolic dysregulation in ischemic retinopathy

Liliana P. Paris, Caroline H. Johnson, Edith Aguilar, Yoshihiko Usui, Kevin Cho, Lihn T. Hoang, Daniel Feitelberg, H. Paul Benton, Peter D. Westenskow, Toshihide Kurihara, Jennifer Trombley, Kinya Tsubota, Shunichiro Ueda, Yoshihiro Wakabayashi, Gary J. Patti, Julijana Ivanisevic, Gary Siuzdak, Martin Friedlander

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

Abstract

Proliferative diabetic retinopathy (PDR) is the most severe form of diabetic retinopathy and, along with diabetic macular edema, is responsible for the majority of blindness in adults below the age of 65. Therapeutic strategies for PDR are ineffective at curtailing disease progression in all cases; however a deeper understanding of the ocular metabolic landscape in PDR through metabolomic analysis may offer new therapeutic targets. Here, global and targeted mass spectrometry-based metabolomics were used to investigate metabolism. Initial analyses on vitreous humor from patients with PDR (n = 9) and non-diabetic controls (n = 11) revealed an increase of arginine and acylcarnitine metabolism in PDR. The oxygen-induced-retinopathy (OIR) mouse model, which exhibits comparable pathological manifestations to human PDR, revealed similar increases of arginine and other metabolites in the urea cycle, as well as downregulation of purine metabolism. We validated our findings by targeted multiple reaction monitoring and through the analysis of a second set of patient samples [PDR (n = 11) and non-diabetic controls (n = 20)]. These results confirmed a predominant and consistent increase in proline in both the OIR mouse model and vitreous samples from patients with PDR, suggesting that over activity in the arginine-to-proline pathway could be used as a therapeutic target in diabetic retinopathy.

Original languageEnglish
Article number15
Pages (from-to)1-10
Number of pages10
JournalMetabolomics
Volume12
Issue number1
DOIs
Publication statusPublished - 2016 Jan 1
Externally publishedYes

Keywords

  • Arginine metabolism
  • Pathway enrichment analysis
  • Proliferative diabetic retinopathy
  • Untargeted metabolomics

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Clinical Biochemistry

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