TY - JOUR
T1 - Global metabolomics reveals metabolic dysregulation in ischemic retinopathy
AU - Paris, Liliana P.
AU - Johnson, Caroline H.
AU - Aguilar, Edith
AU - Usui, Yoshihiko
AU - Cho, Kevin
AU - Hoang, Lihn T.
AU - Feitelberg, Daniel
AU - Benton, H. Paul
AU - Westenskow, Peter D.
AU - Kurihara, Toshihide
AU - Trombley, Jennifer
AU - Tsubota, Kinya
AU - Ueda, Shunichiro
AU - Wakabayashi, Yoshihiro
AU - Patti, Gary J.
AU - Ivanisevic, Julijana
AU - Siuzdak, Gary
AU - Friedlander, Martin
N1 - Funding Information:
We would like to thank Michele Gerhart for administrative support. This work was funded by the US National Institutes of Health (NIH), National Eye Institute EY 11254 (M. F), R01 CA170737 (G. S.), R24 EY017540 (M. F., G. S.), P30 MH062261 (G. S.), RC1 HL101034 (G. S.), and P01 DA026146 (G. S.), California Institute of Regenerative Medicine Grant No. TR1-01219 (G. S.) and the Lowy Medical Research Institute. Financial support was also received from the following Portuguese agencies: the Calouste Gulbenkian Foundation, The Champalimaud Foundation, Ministério da Saúde and Fundação para a Ciência e Tecnologia (fellowship to L. P. P). The Manpei Suzuki Diabetes Foundation and the Alcon Japan Hida Memorial Award (fellowship to Y. U).
Publisher Copyright:
© 2015, The Author(s).
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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.
AB - 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.
KW - Arginine metabolism
KW - Pathway enrichment analysis
KW - Proliferative diabetic retinopathy
KW - Untargeted metabolomics
UR - http://www.scopus.com/inward/record.url?scp=84947432371&partnerID=8YFLogxK
U2 - 10.1007/s11306-015-0877-5
DO - 10.1007/s11306-015-0877-5
M3 - Article
AN - SCOPUS:84947432371
SN - 1573-3882
VL - 12
SP - 1
EP - 10
JO - Metabolomics
JF - Metabolomics
IS - 1
M1 - 15
ER -