Uric acid and ammonia play synergistic roles in the loss of blood-brain barrier integrity in the context of hepatic encephalopathy

The blood-brain barrier (BBB) maintains brain homeostasis by regulating molecular entry. Its endothelial cells are joined by tight junction proteins and express few apical transporters. Hyperuricemia, known to impair tight junctions and endothelial function, may similarly affect the BBB. While ammonia freely diffuses across the BBB, its impact on endothelial integrity is unclear. This study investigates the combined effects of uric acid (UA) and ammonia on BBB function. The BBB integrity in bile-duct ligated rats with hyperuricemia was investigated by evaluating permeability to UA, endothelial cell apoptosis and expression of tight junction proteins in the cerebral cortex. To mimic the conditions described in BDL rat, cultured primary rat brain microvascular endothelial cells (RBMEC), cells were exposed to UA (300 µmol/L) and ammonia (200 or 800 µmol/L) for 20 h prior to assessing the endothelial layer resistance, cell viability and expression of tight junction proteins. Both BDL rats and RBMEC cells exposed to UA and ammonia present with a significant loss of BBB integrity shown by an increased permeability to UA in rats and a decrease endothelial layer resistance in cells. Additionally, both in rats and RBMEC exposure to UA increases endothelial cell apoptosis and exposure to ammonia decreases the expression and integrity of tight junction proteins. The effects of uric acid on endothelial cell viability and of ammonia on tight junction integrity leads to a combined effect of both these molecules on the integrity of the BBB.