Kallikrein-Kinin System: An Emerging Competitor or Collaborator for VEGF in Diabetic Macular Edema?

An increasing number of patients with diabetes suffer from vision-threatening diabetic retinopathy (DR), i.e., proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME), worldwide (1). Vascular endothelial growth factor (VEGF) plays a key role in the angiogenic responses in PDR, and the development of anti-VEGF ther-apy has reduced the burdens of PDR patients (2,3). Retinal vascular permeability leads to morphological and functional damages in the neuroglial components in the retinas and concomitant visual disturbance in DME (4–6). Although anti-VEGF agents have been effective for many patients with DME, their effects are often slow and partial and the benefits are limited, suggesting that there are other cellular and molecular mechanisms in addition to VEGF (7). Diabetes-induced disruption of the blood-retinal bar-