Brain-derived neurotrophic factor modulates angiotensin signaling in the hypothalamus to increase blood pressure in rats

Abstract

Brain-derived neurotrophic factor (BDNF) expression increases in the paraventricular nucleus of the hypothalamus (PVN) in response to hypertensive stimuli including stress and hyperosmolarity. However, it is unclear whether BDNF in the PVN contributes to increases in blood pressure (BP). We tested the hypothesis that increased BDNF levels within the PVN would elevate baseline BP and heart rate (HR) and cardiovascular stress responses by altering central angiotensin signaling. BP was recorded using radiotelemetry in male Sprague-Dawley rats after bilateral PVN injections of adeno-associated viral vectors expressing green fluorescent protein (GFP) or myc epitope-tagged BDNF fusion protein. Cardiovascular responses to acute stress were evaluated 3 to 4 wk after injections. Additional GFP and BDNF-treated animals were equipped with osmotic pumps for intracerebroventricular infusion of saline or the angiotensin type-1 receptor (AT1R) inhibitor losartan (15 μg·0.5 μl(-1)·h(-1)). BDNF treatment significantly increased baseline BP (121 ± 3 mmHg vs. 99 ± 2 mmHg in GFP), HR (394 ± 9 beats/min vs. 314 ± 4 beats/min in GFP), and sympathetic tone indicated by HR- and BP-variability analysis and adrenomedullary tyrosine hydroxylase protein expression. In contrast, body weight and BP elevations to acute stressors decreased. BDNF upregulated AT1R mRNA by ∼80% and downregulated Mas receptor mRNA by ∼50% in the PVN, and losartan infusion partially inhibited weight loss and increases in BP and HR in BDNF-treated animals without any effect in GFP rats. Our results demonstrate that BDNF overexpression in the PVN results in sympathoexcitation, BP and HR elevations, and weight loss that are mediated, at least in part, by modulating angiotensin signaling in the PVN.

Potential unfavorable impacts of BDNF Val66Met polymorphisms on metabolic risks in average population in a longevous area

“…On the contrary, Met allele was either linked to thin phenotype in British females, Chinese Han adolescents and Korean smokers [30–32] or lacked of relationship with obesity in German extremely obese children and adolescents and underweight students [33]. The inconsistency of these results indicates the uncertain association between BDNF Val66Met and obese phenotype which might be modulated by other factors such as ethnic background, age, gender, living environment, dietary structure and lifestyle [34]. Intriguingly, the Met allele carriers in OG exhibited a lower BMI level, implying that the descendants of nonagenarians may endow other unraveled buffering genotypes which may attenuate the unfavorable effect of this variant.…”

Central TrkB blockade attenuates ICV angiotensin II-hypertension and sympathetic nerve activity in male Sprague-Dawley rats

“…Neurotrophic factors not only contribute to synaptic connectivity but also mediate changes in neuronal excitability (Benarroch, 2015; Blum et al, 2005; Cao et al, 2010; Rose et al, 2004). To this end, recent studies have investigated the contribution of the ubiquitous neurotrophin brain-derived neurotrophic factor (BDNF) toward promoting autonomic imbalance during RAS activation (Becker et al, 2016; Becker et al, 2015; Clayton et al, 2014; Erdos et al, 2015a; Schaich et al, 2016). …”

Effects of Blood Pressure Lowering With Different Antihypertensive Agents on Cognitive Function and Plasma Brain-derived Neurotrophic Factor Levels

“…36 A new study has shown a connection between RAS and BDNF, where BDNF modulates angiotensin signaling. 37 At the same time, there are studies suggesting the neuro-protective actions of RAS blockers involving BDNF. 38,39 Considering all together, there are no clinical studies that have explored the direct relationship between RAS and BDNF.…”