Antidepressant-like effect of losartan involves TRKB transactivation from angiotensin receptor type 2 (AGTR2) and recruitment of FYN

Abstract

Renin-angiotensin system (RAS) is associated to peripheral fluid homeostasis and cardiovascular function, but recent evidence has also drawn its functional role in the brain. RAS has been described to regulate physiological and behavioral parameters related to stress response, including depressive symptoms. Apparently, RAS can modulate levels of brain derived neurotrophic factor (BDNF) and TRKB, which are important to neurobiology of depression and antidepressant action. However, interaction between BDNF/TRKB system and RAS in models predictive of antidepressant effect has not been investigated before. Accordingly, in the forced swimming test, we observed an antidepressant-like effect of systemic losartan but not with captopril or enalapril treament. Moreover, infusion of losartan into ventral hippocampus (vHC) and prelimbic prefrontal cortex (PL) mimicked the consequences of systemically injected losartan, whereas K252a, a blocker of TRK, infused into these brain areas impaired such effect. PD123319, an antagonist of AT2 receptor (AGTR2), infused into PL but not into vHC, also prevented systemic losartan effect. Cultured cortical cells of rat embryos indicate that angiotensin II (ANG2), possibly through AGTR2, increases the surface levels of TRKB, and favors its coupling to FYN, a SRC family kinase. The higher levels of agtr2 in cortical cells were decreased after insult with glutamate, and under this condition an interaction between losartan and ANG2 was achieved. Occurrence of TRKB/AGTR2 heterodimers was also observed, in MG87 cells GFP-tagged AGTR2 co-immunoprecipitated with TRKB. Therefore, antidepressant-like effect of losartan is proposed to occur through a shift of ANG2 binding towards AGTR2, followed by coupling of TRK/FYN and putative TRKB transactivation. Thus, AGTR1 show therapeutic potential as novel antidepressant therapy.