Prominent arginine-proline metabolic pathway perturbations characterize human proliferative diabetic retinopathy and the oxygen-induced-retinopathy mouse model

Abstract

Purpose: To generate a local metabolic fingerprint of proliferative diabetic retinopathy (PDR) and to identify novel therapeutic targets with potential to improve patient care.

Methods: Vitreous samples from twenty patients with proliferative diabetic retinopathy and twenty-seven from non-diabetic controls were collected, immediately frozen in liquid nitrogen and later analyzed by a highly sensitive mass-spectrometry based metabolomics approach. Clinical data and blood samples were collected for each patient. Whole eyes and isolated retinas from the OIR mouse model or age-matched C57/Bl6 controls were collected at P12, P14 and P17 and analyzed using the same metabolomics approach.

Results: Vitreous samples from PDR patients were clearly distinguishable from those of non-diabetic controls by prominent and consistent metabolic perturbations.<br /> The metabolomic phenotype of PDR was characterized by significant disturbances in amino acid metabolism, acylcarnitines, purine metabolism-related-oxidative stress and ammonia detoxification pathways. In the vitreous of PDR patients there was a statistically significant upregulation of free amino acids such as arginine, citrulline, ornithine, and proline (all elements of the arginine-proline pathway) as well as methionine. A significant upregulation of long chain acylcarnitines (octanoylcarnitine and decanoylcarnitine) and of allantoin was also observed along with a significant downregulation in N-Acetyl-Glutamate and N-Acetyl-Aspartate.<br /> Similarly, ocular samples from the OIR mouse model revealed a significant upregulation in amino acids, such as arginine, proline, citrulline, lysine and in acylcarnitine levels (octanoylcarnitine, propionylcarnitine and acetylcarnitine).

Conclusions: Major defects in amino acid, lipid and purine metabolism pathways are found in the vitreous from PDR patients and clearly demarcate them from non-diabetic controls, suggesting that these changes may play an important role in disease development and/or progression<br /> These findings provide new insights into the metabolic state of the eye in PDR and will help identify novel biomarkers and druggable targets, contributing to development of new and more effective therapies.<br /> The OIR mouse shares relevant metabolic perturbations with human PDR, suggesting that it can be a suitable model for identifying novel therapeutic targets