Sustained pharmacological inhibition of δPKC protects against hypertensive encephalopathy through prevention of blood-brain barrier breakdown in rats
Xin Qi, … , Raymond A. Sobel, Daria Mochly-Rosen
Xin Qi, … , Raymond A. Sobel, Daria Mochly-Rosen
Published December 20, 2007
Citation Information: J Clin Invest. 2008;118(1):173-182. https://doi.org/10.1172/JCI32636.
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Research Article

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

Abstract

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 δPKC, which is thought to regulate microvascular permeability, in the development of hypertensive encephalopathy using δV1-1 — a selective peptide inhibitor of δPKC. 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 δV1-1 using osmotic minipumps. The mortality rate and the behavioral symptoms of hypertensive encephalopathy decreased significantly in the δV1-1–treated group relative to the control-treated group, and BBB permeability was reduced by more than 60%. Treatment with δV1-1 was also associated with decreased δPKC accumulation in capillary endothelial cells and in the endfeet of capillary astrocytes, which suggests decreased microvasculature disruption. Treatment with δV1-1 prevented hypertension-induced tight junction disruption associated with BBB breakdown, which suggests that δPKC may specifically act to dysregulate tight junction components. Together, these results suggest that δPKC plays a role in the development of hypertension-induced encephalopathy and may be a therapeutic target for the prevention of BBB disruption.

Authors

Xin Qi, Koichi Inagaki, Raymond A. Sobel, Daria Mochly-Rosen

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Figure 2

Sustained delivery of δV1-1 peptide inhibits hypertension-induced δPKC translocation.

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Sustained delivery of δV1-1 peptide inhibits hypertension-induced δPKC t...
Rats fed a high-salt diet were treated with δV1-1, saline, or TAT as in Figure 1. Brain tissue was harvested at 13 weeks of age. (A) Soluble and particulate fractions of brain tissue were subjected to Western blot analysis, and δPKC translocation was determined. The blots show representative results, and the graph provides quantification of δPKC translocation from the cytosolic to the membranal fractions. Data are mean ± SEM (n = 3 rats per group). F = 13.68, df = 3. *P < 0.05 versus saline or TAT treatment; #P < 0.05 versus rats fed a low-salt diet (Nor). GAPDH and Gα were used as internal controls for cytosolic and membranal fractions, respectively. (B) Total lysates of the brain were subjected to Western blot analysis with anti-δPKC. GAPDH was used as an internal loading control. Representative data are from 3 rats per group. (C) Phosphorylation of δPKC (Ser643) was determined by Western blot analysis. Data are mean ± SEM (n = 3 rats per group). F = 11.49, df = 3. *P < 0.05 versus saline treatment groups; #P < 0.05 versus rats fed a low-salt diet.