Hypothalamic kinin B1 receptor mediates orexin system hyperactivity in neurogenic hypertension.

Abstract

Brain orexin system hyperactivity contributes to neurogenic hypertension. We previously reported upregulated neuronal kinin B1 receptor (B1R) expression in hypertension. However, the role of central B1R activation on the orexin system in neurogenic hypertension has not been examined. We hypothesized that kinin B1R contributes to hypertension via upregulation of brain orexin-arginine vasopressin signaling. We utilized deoxycorticosterone acetate (DOCA)-salt hypertension model in wild-type (WT) and B1R knockout (B1RKO) mice. In WT mice, DOCA-salt-treatment increased gene and protein expression of orexin A, orexin receptor 1, and orexin receptor 2 in the hypothalamic paraventricular nucleus and these effects were attenuated in B1RKO mice. Furthermore, DOCA-salt- treatment increased plasma arginine vasopressin levels in WT mice, but not in B1RKO mice. Cultured primary hypothalamic neurons expressed orexin A and orexin receptor 1. B1R specific agonist (LDABK) stimulation of primary neurons increased B1R protein expression, which was abrogated by B1R selective antagonist R715 but not by the dual orexin receptor antagonist, ACT 462206, suggesting that B1R is upstream of the orexin system. These data provide novel evidence that B1R blockade blunts orexin hyperactivity and constitutes a potential therapeutic target for the treatment of salt-sensitive hypertension.

• Authors: Rohan Umesh Parekh, Acacia White, Korin E Leffler, Vinicia C Biancardi, Jeffrey B Eells, Abdel A Abdel-Rahman, Srinivas Sriramula
• Journal: Scientific reports (Sci Rep) Vol. 11 Issue 1 Pg. 21050 (10 26 2021) ISSN: 2045-2322 [Electronic] England
• PMID: 34702886 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2021. The Author(s).

Chemical References

• Orexins
• Receptor, Bradykinin B1

Topics

• Animals
• Disease Models, Animal
• Gene Expression Regulation
• Hypertension (chemically induced, drug therapy, genetics, metabolism)
• Hypothalamus (metabolism)
• Mice
• Mice, Knockout
• Neurons (metabolism)
• Orexins (genetics, metabolism)
• Receptor, Bradykinin B1 (biosynthesis, genetics)