Microglia Mediate Hypertension and Autonomic Dysfunction through Kinin B1 Receptor Activation

Reactive oxygen species and proinflammatory cytokines in the central nervous system can induce or exacerbate hypertension (HTN) and result in autonomic dysfunction. During HTN, activated microglia modulates autonomic neural activity in the paraventricular nucleus of the hypothalamus (PVN) by regulating neuroinflammation and blood pressure. We previously reported that enhanced kinin B1 receptor (B1R) expression in the brain is associated with increased neuroinflammation and autonomic dysfunction leading to the development of HTN. However, the functional role of B1R within microglia and signaling mechanisms during HTN have yet to be investigated. In this study, we tested the hypothesis that B1R blockade will reduce oxidative stress and mitochondrial dysfunction in microglia, resulting in an attenuation of hypertension and improved autonomic function. Male and female C57BL/6NJ wild-type (WT) and B1R global gene deficient mice (B1RKO) were administered angiotensin II (Ang II) (600 ng/kg/min; SC, 2 weeks) or saline (vehicle) via osmotic minipumps. Ang II infusion significantly increased mean arterial pressure (radiotelemetry) in WT mice (145 ±13 mmHg vs. 103 ±6, n=6, p<0.01), which was attenuated in B1RKO mice. Ang II induced HTN resulted in dysautonomia as indicated by significantly increased plasma norepinephrine levels (p<0.05, n=6) and decreased spontaneous baroreceptor reflex sensitivity (p<0.05, n=6). This further suggests that B1R contributes to impaired autonomic and baroreflex functions in HTN. In addition, CX3CR1 expression in the PVN revealed that microglia-neuron interactions may be increased during HTN. TMEM119 immunofluorescence revealed significant morphological changes in microglia in the PVN of Ang II infused mice compared to saline controls (p<0.05, n=3). To further define the role of microglia, we cultured primary microglia from neonatal mice and found that Ang II induces mitochondrial oxidative stress (MitoSOX) and decreases mitochondrial membrane potential (TMRE) (p<0.01, n=4), however use of B1R specific antagonist SSR240612 was able to reduce these responses. This data coincides with previous data published in primary hypothalamic neurons. To then explore the role of neuron-microglia interactions following Ang II stimulation, we established a direct co-culturing method and through immunocytochemistry, confirmed that levels of oxidative stress and inflammation were significantly increased in our co-culture model compared to when cultured individually (p<0.05, n=3). Pretreatment with B1R antagonist was able to attenuate these effects. This data indicates that autonomic and mitochondrial dysfunction may be regulated, in part, through the kinin B1 receptor in microglia and that neuron-microglia interactions can enhance these effects. This allows us to believe that B1R blockade may serve as a potential therapeutic target for HTN induced mitochondrial and autonomic dysfunction. This study was supported by the NHLBI/NIH 5R01HL153115 (S. Sriramula). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.