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Takeshi Kita, Allen C. Clermont, Kimihiko Fujisawa, Tatsuro Ishibashi, Lloyd P. Aiello, Edward P. Feener; Heterogeneity of the Vitreous Proteome in Diabetic Macular Edema Correlates with Levels of Plasma Kallikrein and VEGF. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3569.
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We previously demonstrated that plasma kallikrein-kinin system (KKS) components including plasma kallikrein (PK) are increased in the vitreous of patients with diabetic macular edema (DME). In this study we examined the correlation among PK, VEGF, and other components of the vitreous proteome and examined the role of bradykinin receptors on VEGF action in the retina.
Vitreous from subjects with DME without proliferative diabetic retinopathy (n=10) and nondiabetic subjects with macular hole (n=5) were analyzed by mass spectrometry-based proteomics. Correlations with VEGF and PK levels were performed on proteins detected in at least 3 of the DME samples. Effects on retinal vascular permeability (RVP) and retinal thickness following intravitreal VEGF injection [with or without co-injection of bevacizumab or systemic administration of des-Arg-Hoe140 (B1R antagonist) and Hoe140 (B2R antagonist)] were analyzed in streptozotocin-induced diabetic rats by vitreous fluorophotometry and spectral domain optical coherence tomography (SD-OCT), respectively.
Vitreous PK levels did not correlate with VEGF levels. We identified subgroups of DME patients with high PK and lower VEGF, or high VEGF and lower PK. Elevated protein concentrations in the DME vitreous correlated with increased intravitreal PK levels (r=0.73, p=0.003), but not with VEGF levels. Proteomic analysis identified 291 proteins and revealed that VEGF and PK were associated with independent groups of vitreous proteins. We found that 13 proteins including crystallins were correlated with VEGF levels, and 4 different proteins including isoform 1 of fibronectin correlated with PK levels. In addition, 7 proteins including retinoschisin and beta-crystallin S were positively correlated with VEGF levels and negatively correlated with PK levels. VEGF intravitreal injection increased RVP (2.6 fold, p<0.001) 40 minutes after injection and retinal thickness 24 hours after injection, responses blocked by bevacizumab but unaffected by bradykinin receptor antagonists.
These results demonstrate DME vitreous proteome heterogeneity with regard to VEGF and PK concentration. Subgroups of DME patients may be characterized according to levels of PK, VEGF, and the composition of the vitreous proteome. This heterogeneity might account in part for variability of clinical response to anti-VEGF agents.
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