Increase in Blood–Brain Barrier Permeability is Modulated by Tissue Kallikrein via Activation of Bradykinin B1 and B2 Receptor-Mediated Signaling

AIM: Disruption of the blood–brain barrier (BBB) is a critical pathological feature after stroke. Although tissue kallikrein (TK) has used in the treatment of stroke in China, the role of TK in modulating BBB permeability is not clear. METHODS: We investigated the effect of different doses of TK on BBB by in vivo assessments of Evans blue (EB) and sodium-fluorescein isothiocyanate (FITC) leakage and in vitro assessments of the integrity of BBB and monolayers of microvascular endothelial cells (BMVECs). The expression of zonula occludens-1 (ZO-1) and bradykinin receptor-mediated signaling in BMVECs was detected. RESULTS: A significant increase in BBB permeability was observed in the mice treated with high dose of TK. However, standard and medium doses of TK could only enable sodium-FITC to enter the brain. The result of in vitro study indicated that high-doses of TK, but not standard and medium-dose of TK, reduced normal BBB integrity accompanied by a decreased expression of zonula occludens-1 (ZO-1), upregulated the mRNA levels of bradykinin 2 receptor (B2R) and endothelial nitric oxide synthase (eNOS) and the abundance of B2R. Moreover, standard-dose of TK exacerbated lipopolysaccharide-induced BBB hyperpermeability, upregulated the mRNA levels of bradykinin 1 receptor (B1R) and inducible nitric oxide synthase (iNOS), increased the abundance of B1R and reduced the abundance of ZO-1; these effects were inhibited by TK inhibitor. CONCLUSION: TK can disrupt tight junctions and increase normal BBB permeability via B2R-dependent eNOS signaling pathway, aggravate impairment of BBB via B1R-dependent iNOS signaling pathway, and consequently serve as a useful adjunctive treatment for enhancing the efficacy of other neurotherapeutics.