Transcriptional upregulation of brain-derived neurotrophic factor in rostral ventrolateral medulla by angiotensin II: Significance in superoxide homeostasis and neural regulation of arterial pressure

Rationale: Oxidative stress in rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons for the maintenance of neurogenic vasomotor tone are located, contributes to neural mechanisms of hypertension. Emerging evidence suggests that brain-derived neurotrophic factor (BDNF) manifests "nontrophic" actions. Objective: We assessed the hypothesis that BDNF plays an active role in oxidative stress-associated neurogenic hypertension by maintaining superoxide anion ((Equation is included in full-text article.)) homeostasis in RVLM. Methods and Results: In Wistar-Kyoto rats, microinjection of angiotensin II (Ang II) bilaterally into RVLM upregulated BDNF mRNA and protein and induced cAMP response element binding protein (CREB) phosphorylation. The Ang II-induced BDNF upregulation in RVLM was attenuated by coadministration of the NADPH oxidase inhibitor apocynin; the superoxide dismutase mimetic tempol; or an antisense oligonucleotide against CREB. Intracisternal infusion of Ang II elicited phosphorylation of p47 subunit of NADPH oxidase, suppression of mitochondrial electron coupling capacity, and augmentation in mitochondrial uncoupling protein (UCP)2 expression in RVLM. The former 2 cellular events were enhanced, whereas UCP2 upregulation was attenuated by gene knockdown of BDNF or depletion of tropomyosin receptor kinase (Trk)B ligands with recombinant human TrkB-Fc fusion protein. The same treatments also significantly potentiated both Ang II-induced (Equation is included in full-text article.)production in RVLM and chronic pressor response. Conclusions: Ang II induces (Equation is included in full-text article.)-dependent upregulation of BDNF in RVLM via phosphorylation of CREB. The Ang II-activated BDNF/TrkB signaling, in turn, exerts negative-feedback regulation on tissue (Equation is included in full-text article.)level in RVLM through inhibition of p47 phosphorylation, preservation of mitochondrial electron transport capacity, and upregulation of mitochondrial UCP2, resulting in protection against Ang II-induced oxidative stress and long-term pressor response.