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

Abstract

ObjectiveThis 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.MethodsAdult 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.ResultsCompared 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.ConclusionsThis 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.