Abstract
Purpose:
Vasoinhibins are proteolytically-derived fragments of the hormone prolactin that prevent excessive retinal vasopermeability (RVP) associated with diabetes (JCI 118:2291, 2008). The kallikrein-kinin system has been shown to contribute to RVP increase associated with diabetes by enhancing bradykinin (BK) production (Nat Med 13:181, 2007) and inducing B1 receptor expression (PloS One 7:e33864, 2012). Here we investigated if vasoinhibins could attenuate the increase of RVP induced by the intravitreal injection of BK as well as the induction of B1 receptor expression in diabetes.
Methods:
The RVP was quantified by the Evans blue method in Wistar male rats that were injected intravitreously with BK (1 nM), combined or not with vasoinhibins (1 µM) or a B2 receptor antagonist (HOE-140). The retinal expression of B1 receptor mRNA was quantified by real-time pcr in two models: 1) healthy rats intravitreously injected with vitreous from patients with proliferative diabetic retinopathy (PDR) for 48 h, and 2) rats rendered diabetic by i.p. streptozotocin for 4 weeks. Both models were also subjected to intra-vitreous injection of vasoinhibins for the last 24 h.
Results:
Intravitreal injection of BK resulted in a two-fold increase in RVP compared to saline. Vasoinhibins prevented the BK effect on RVP, as did the B2 receptor antagonist Hoe-140. In addition, mRNA levels of B1 receptor were increased by four- and two-fold in retinas from rats injected with vitreous from PDR patients and diabetic rats compared to rats injected with vitreous from non-diabetic patients and controls, respectively. Notably, vasoinhibins prevented the induction of B1 receptor expression in both models.
Conclusions:
Vasoinhibins reduce the BK-induced increase of RVP and the induction of B1 receptor expression related to diabetes.
Keywords: 499 diabetic retinopathy •
715 signal transduction: pharmacology/physiology •
498 diabetes