Sustained pharmacological inhibition of deltaPKC 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 deltaPKC, which is thought to regulate microvascular permeability, in the development of hypertensive encephalopathy using deltaV1-1 - a selective peptide inhibitor of deltaPKC. 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 deltaV1-1 using osmotic minipumps. The mortality rate and the behavioral symptoms of hypertensive encephalopathy decreased significantly in the deltaV1-1-treated group relative to the control-treated group, and BBB permeability was reduced by more than 60%. Treatment with deltaV1-1 was also associated with decreased deltaPKC accumulation in capillary endothelial cells and in the endfeet of capillary astrocytes, which suggests decreased microvasculature disruption. Treatment with deltaV1-1 prevented hypertension-induced tight junction disruption associated with BBB breakdown, which suggests that deltaPKC may specifically act to dysregulate tight junction components. Together, these results suggest that deltaPKC plays a role in the development of hypertension-induced encephalopathy and may be a therapeutic target for the prevention of BBB disruption.
Qi
Xin
X
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
Inagaki
Koichi
K
Sobel
Raymond A
RA
Mochly-Rosen
Daria
D
D000818:Animals; D001812:Blood-Brain Barrier / Q000201:enzymology* / Q000473:pathology; D001929:Brain Edema / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects; D004730:Endothelium, Vascular / Q000201:enzymology / Q000473:pathology; D020343:Hypertensive Encephalopathy / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D009842:Oligopeptides / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D051381:Rats; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D019108:Tight Junctions / Q000201:enzymology / Q000473:pathology
D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; C477270:Ser-Phe-Asn-Ser-Tyr-Glu-Leu-Gly-Glu-Ser-Leu; C497260:Prkcd protein, rat; D051745:Protein Kinase C-delta