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Kinin B1 Receptor Blockade Attenuates Hypertension via Angiotensin II Mediated Signaling in Neurons
Author(s) -
Parekh Rohan Umesh,
Sriramula Srinivas
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.00010
Subject(s) - endocrinology , medicine , angiotensin ii , kinin , blood pressure , agonist , renin–angiotensin system , receptor , chemistry , bradykinin
Interaction between renin‐angiotensin system (RAS) and kallikrein‐kinin system (KKS) has been shown to play an important role in the regulation of blood pressure. We previously reported that kinin B1 receptor (B1R) expression is increased in the neurons of hypertensive mice with elevated angiotensin II (Ang II) levels in the brain. However, the role of B1R in neurogenic hypertension and its interaction with Ang II type 1 receptor (AT1R), the major receptor of Ang II, have not been studied. Ang II treatment (1 μg/kg/min, SC, 2 weeks) significantly increased blood pressure (radiotelemetry) in male wild‐type (WT) mice (145 ±13 mmHg, n=6, p<0.01) compared to control mice (103 ±6 mmHg, n=6). This increase in blood pressure was attenuated in B1R knockout (B1RKO) mice with Ang II infusion (118 ±12 mmHg, n=6, p<0.01). In addition, B1R knockdown significantly reduced Ang II‐induced AT1R expression and vasopressin levels. In order to further confirm the causative role of B1R on inducing hypertension, we used a specific B1R agonist Lys‐des‐Arg 9 ‐BK (LDABK) to activate central B1R and measured blood pressure response using telemetry transmitters. A single bolus intracerebroventricular injection of 50 ng of LDABK, significantly increased blood pressure compared to artificial cerebrospinal fluid (18 ±5 mmHg vs. 4 ±2 mmHg, n=6, p<0.01), supporting the hypothesis that B1R activation can induce hypertensive response. To further understand the neuron specific B1R mediated signaling, we isolated mouse neonatal primary hypothalamic neuronal cultures from WT and B1RKO mice and investigated the interaction between Ang II and B1R activation. Stimulation of primary neurons with LDABK (300 nM, 24 h), significantly increased the expression of AT1R mRNA (3‐fold vs. vehicle; n=6; p<0.05) and resulted in neuroinflammation as indicated by upregulated expression of inflammatory markers interleukin (IL)‐1β, IL‐6, tumor necrosis factor, and monocyte chemoattractant protein 1. These changes were attenuated in B1RKO neurons or pretreatment of WT neurons with R715 (a B1R specific peptide antagonist). Together, these data provide novel evidence that kinin B1R plays an important role in mediating hypertension possibly via modulating angiotensin signaling in the brain.