Retinal plasma extravasation in streptozotocin‐diabetic rats mediated by kinin B1 and B2 receptors

Background and purpose: We investigated whether or not kinin receptors play a role in diabetic blood–retinal barrier breakdown, which is a leading cause of vision loss. Experimental approach: Blood–retinal barrier breakdown was quantified using Evans blue, and expression of kinin B1 receptor mRNA was measured using quantitative reverse transcrition‐PCR. Diabetic rats (streptozotocin (STZ), 65 mg kg−1) received a single intraocular injection of bradykinin (BK) or des‐Arg9‐BK, alone, or in combination with antagonists for B1 (des‐Arg10‐Hoe140, R‐715) and/or B2 (Hoe140) receptors, given intraocularly or intravenously (i.v.). Key results: In control rats, BK (0.1–10 nmol) dose‐dependently increased plasma extravasation, which was inhibited by Hoe140 (0.2 nmol), whereas des‐Arg9‐BK (0.1 and 1 nmol) was without effect. B1 receptor mRNA was markedly increased in retinas of diabetic rats, and this was prevented by N‐acetyl‐L‐cysteine (1 g kg−1 day−1 for 7 days). Plasma extravasation in retinas of STZ‐diabetic rats was higher than in controls and enhanced by des‐Arg9‐BK. Response to des‐Arg9‐BK was inhibited by intraocular or i.v. injection of B1 receptor antagonists. Diabetes‐induced plasma extravasation was inhibited only by a combination of des‐Arg10‐Hoe140 and Hoe 140 (100 nmol kg−1, i.v. 15 min earlier) or by R‐715 (1 μmol kg−1, i.v.) injected daily for 7 days. Conclusions and implications: Kinin B1 receptors are upregulated in retinas of STZ‐diabetic rats through a mechanism involving oxidative stress. Both kinin B1 and B2 receptors contribute to increased plasma extravasation in diabetic retinopathy. Chronic inhibition of both kinin receptors, possibly with antioxidant adjuvants, may be a novel therapeutic strategy for diabetic retinopathy.