Sustained pharmacological inhibition of delta PKC protects against hypertensive encephalopathy through prevention of blood-brain barrier breakdown in rats

Hypertensive encephalopathy is a potentially fatal condition associated with cerebral edema and the breakdown of the blood-brain barrier (BBB). The molecular pathways leading to this condition, however, are unknown. We determined the role of delta PKC, which is thought to regulate microvascular permeability, in the development of hypertensive encephalopathy using delta V1-1 - a selective peptide inhibitor of delta PKC. As a model of hypertensive encephalopathy, Dahl salt-sensitive rats were fed an 8% high-salt diet from 6 weeks of age and then were infused s.c. with saline, control TAT peptide, or delta V1-1 using osmotic minipumps. The mortality rate and the behavioral symptoms of hypertensive encephalopathy decreased significantly in the delta V1-1-treated group relative to the control-treated group, and BBB permeability was reduced by more than 60%. Treatment with delta V1-1 was also associated with decreased delta PKC accumulation in capillary endothelial cells and in the endfeet of capillary astrocytes, which suggests decreased microvasculature disruption. Treatment with delta V1-1 prevented hypertension-induced tight junction disruption associated with BBB breakdown, which suggests that delta PKC may specifically act to dysregulate tight junction components. Together, these results suggest that delta PKC plays a role in the development of hypertension-induced encephalopathy and may be a therapeutic target for the prevention of BBB disruption.