Angiotensin-(1–7) suppresses pyroptosis in cerebral endothelium to decrease blood–brain barrier permeability and cognitive impairments in sepsis

Objective This study aimed to explore the influence of the angiotensin-(1–7)/Mas receptor and angiotensin II/angiotensin II type 1 receptor pathways on pyroptosis during sepsis and their subsequent effects on cognitive function. Methods Adult C57BL/6 mice were subjected to cecal ligation and puncture to induce sepsis. Brain microvascular endothelial cells were treated with angiotensin II and angiotensin-(1–7) to evaluate their impact on pyroptotic processes. Cognitive performance was assessed using the Morris water maze method, and blood–brain barrier permeability was quantified using Evans blue staining. Results Compared with the sham group, sepsis induced sustained activation of the angiotensin II/angiotensin II type 1 receptor pathway, whereas the angiotensin-(1–7)/Mas receptor pathway was progressively suppressed. Genetic ablation of cysteine-dependent aspartate protease-1 significantly attenuated pyroptosis in brain endothelial cells, decreased blood–brain barrier permeability, and enhanced cognitive function in septic mice compared with that in the cecal ligation and puncture group. Angiotensin-(1–7) treatment improved cognitive function in septic mice and significantly suppressed angiotensin II-induced pyroptosis, with these effects reversed by the Mas receptor antagonist A-779. Conclusions This study identified a novel mechanism in which angiotensin-(1–7) selectively suppresses angiotensin II-induced pyroptosis in brain endothelial cells, consequently ameliorating cognitive deficits during sepsis.