title: Global metabolomics reveals metabolic dysregulation in ischemic retinopathy.
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.
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, MB 28, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA.
authors.forename: Liliana P
authors.initials: LP
authors.lastname: Paris
authors.affiliation: Scripps Center for Metabolomics and Mass Spectrometry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA.
authors.forename: Caroline H
authors.initials: CH
authors.lastname: Johnson
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, MB 28, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA.
authors.forename: Edith
authors.initials: E
authors.lastname: Aguilar
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, MB 28, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA.|Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023 Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Usui
authors.affiliation: Departments of Chemistry, Genetics, and Medicine, Washington University School of Medicine, St. Louis, MO 63110 USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Cho
authors.affiliation: Scripps Center for Metabolomics and Mass Spectrometry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA.
authors.forename: Lihn T
authors.initials: LT
authors.lastname: Hoang
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, MB 28, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Feitelberg
authors.affiliation: Scripps Center for Metabolomics and Mass Spectrometry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA.
authors.forename: H Paul
authors.initials: HP
authors.lastname: Benton
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, MB 28, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA.|The Lowy Medical Research Institute, 3030 N. Torrey Pines Court, La Jolla, CA 92037 USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Westenskow
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, MB 28, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Kurihara
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, MB 28, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA.|The Lowy Medical Research Institute, 3030 N. Torrey Pines Court, La Jolla, CA 92037 USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Trombley
authors.affiliation: Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023 Japan.
authors.forename: Kinya
authors.initials: K
authors.lastname: Tsubota
authors.affiliation: Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023 Japan.
authors.forename: Shunichiro
authors.initials: S
authors.lastname: Ueda
authors.affiliation: Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023 Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Wakabayashi
authors.affiliation: Departments of Chemistry, Genetics, and Medicine, Washington University School of Medicine, St. Louis, MO 63110 USA.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Patti
authors.affiliation: Scripps Center for Metabolomics and Mass Spectrometry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA.
authors.forename: Julijana
authors.initials: J
authors.lastname: Ivanisevic
authors.affiliation: Scripps Center for Metabolomics and Mass Spectrometry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Siuzdak
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, MB 28, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA.|The Lowy Medical Research Institute, 3030 N. Torrey Pines Court, La Jolla, CA 92037 USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Friedlander
keywords: Arginine metabolism; Pathway enrichment analysis; Proliferative diabetic retinopathy; Untargeted metabolomics