BDNF contributes to angiotensin II-mediated reductions in peak voltage-gated K+ current in cultured CATH.a cells

Abstract

Increased central angiotensin II (Ang II) levels contribute to sympathoexcitation in cardiovascular disease states such as chronic heart failure and hypertension. One mechanism by which Ang II increases neuronal excitability is through a decrease in voltage-gated, rapidly inactivating K(+) current (IA); however, little is known about how Ang II signaling results in reduced IA. Brain-derived neurotrophic factor (BDNF) has also been demonstrated to decrease IA and has signaling components common to Ang II. Therefore, we hypothesized that Ang II-mediated suppression of voltage-gated K(+) currents is due, in part, to BDNF signaling. Differentiated CATH.a, catecholaminergic cell line treated with BDNF for 2 h exhibited a reduced IA in a manner similar to that of Ang II treatment as demonstrated by whole-cell patch-clamp analysis. Inhibiting BDNF signaling by pretreating neurons with an antibody against BDNF significantly attenuated the Ang II-induced reduction of IA. Inhibition of a common component of both BDNF and Ang II signaling, p38 MAPK, with SB-203580 attenuated the BDNF-mediated reductions in IA. These results implicate the involvement of BDNF signaling in Ang II-induced reductions of IA, which may cause increases in neuronal sensitivity and excitability. We therefore propose that BDNF may be a necessary component of the mechanism by which Ang II reduces IA in CATH.a cells.

Keywords: AT1R; SB‐203580; TrkB; p38 MAPK.

Figure 1

BDNF and TrkB expression in CATH.a cells following Ang II treatment. Representative blots (C) and relative expression levels of BDNF (A), pro-BDNF (B), and TrkB (D) following treatment of CATH.a cells with 100 nmol/L Ang II for 2 or 6 h. *P < 0.05 versus Control treatment, n = 5–8/group.

Figure 2

Effect of BDNF on I_A. Representative traces (A) and mean I–V plots of peak K⁺ current density (B) in CATH.a neurons treated with 50 ng/mL BDNF for 2 h. *P < 0.05 interaction between groups as measured by RM-ANOVA.

Figure 3

Effect of inhibiting BDNF on Ang II-induced suppression of I_A. Mean I–V plots of peak K⁺ current density of CATH.a neurons incubated with 100 nmol/L Ang II for 6 h or pretreated with 50 ng/mL anti-BDNF antibody for 30 min prior to Ang II. **P < 0.01 group interaction versus Control and ##P < 0.01 versus Ang II group interaction as measured by RM-ANOVA.

Figure 4

Effect of inhibition of MAPK on BDNF-induced reduction of I_A. Mean I–V plots of peak K⁺ current density in CATH.a neurons incubated with 50 ng/mL BDNF for 2 h or pretreated with 100 nmol/L SB-203580 (SB) for 30 min prior to BDNF. *P < 0.05 group interaction between BDNF and SB+BDNF as measured by RM-ANOVA.