Pancreatic kallikrein protects against diabetic retinopathy in KK Cg-A(y)/J and high-fat diet/streptozotocin-induced mouse models of type 2 diabetes

AIMS/HYPOTHESIS: Many studies have shown that tissue kallikrein has effects on diabetic vascular complications such as nephropathy, cardiomyopathy and neuropathy, but its effects on diabetic retinopathy are not fully understood. Here, we investigated the retinoprotective role of exogenous pancreatic kallikrein and studied potential mechanisms of action. METHODS: We used KK Cg-A(y)/J (KKAy) mice (a mouse model of spontaneous type 2 diabetes) and mice with high-fat diet/streptozotocin (STZ)-induced type 2 diabetes as our models. After the onset of diabetes, both types of mice were injected intraperitoneally with either pancreatic kallikrein (KKAy + pancreatic kallikrein and STZ + pancreatic kallikrein groups) or saline (KKAy + saline and STZ + saline groups) for 12 weeks. C57BL/6J mice were used as non-diabetic controls for both models. We analysed pathological changes in the retina; evaluated the effects of pancreatic kallikrein on retinal oxidative stress, inflammation and apoptosis; and measured the levels of bradykinin and B1 and B2 receptors in both models. RESULTS: In both models, pancreatic kallikrein improved pathological structural features of the retina, increasing the thickness of retinal layers, and attenuated retinal acellular capillary formation and vascular leakage (p < 0.05). Furthermore, pancreatic kallikrein ameliorated retinal oxidative stress, inflammation and apoptosis in both models (p < 0.05). We also found that the levels of bradykinin and B1 and B2 receptors were increased after pancreatic kallikrein in both models (p < 0.05). CONCLUSIONS/INTERPRETATION: Pancreatic kallikrein can protect against diabetic retinopathy by activating B1 and B2 receptors and inhibiting oxidative stress, inflammation and apoptosis. Thus, pancreatic kallikrein may represent a new therapeutic agent for diabetic retinopathy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00125-019-4838-9) contains peer reviewed but unedited supplementary material, which is available to authorised users.