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

2017 ◽  
Author(s):  
Cassiano R.A.F Diniz ◽  
Plinio C. Casarotto ◽  
Senem M. Fred ◽  
Caroline Biojone ◽  
Eero Castrén ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Renin Angiotensin System ◽  
Antidepressant Effect ◽  
Cortical Cells ◽  
Angiotensin System ◽  
Behavioral Parameters ◽  
Swimming Test ◽  
Angiotensin Receptor Type 2 ◽  
The Brain

ABSTRACTRenin-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 it’s 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.

scholarly journals The Angiotensin II Type 2 Receptor in Brain Functions: An Update

2012 ◽  
Vol 2012 ◽  
pp. 1-18 ◽  
Author(s):  
Marie-Odile Guimond ◽  
Nicole Gallo-Payet
Keyword(s):  
Angiotensin Ii ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Brain Functions ◽  
Physiological Relevance ◽  
Ang Iv ◽  
The Brain

Angiotensin II (Ang II) is the main active product of the renin-angiotensin system (RAS), mediating its action via two major receptors, namely, the Ang II type 1 (AT1) receptor and the type 2 (AT2) receptor. Recent results also implicate several other members of the renin-angiotensin system in various aspects of brain functions. The first aim of this paper is to summarize the current state of knowledge regarding the properties and signaling of the AT2receptor, its expression in the brain, and its well-established effects. Secondly, we will highlight the potential role of the AT2receptor in cognitive function, neurological disorders and in the regulation of appetite and the possible link with development of metabolic disorders. The potential utility of novel nonpeptide selective AT2receptor ligands in clarifying potential roles of this receptor in physiology will also be discussed. If confirmed, these new pharmacological tools should help to improve impaired cognitive performance, not only through its action on brain microcirculation and inflammation, but also through more specific effects on neurons. However, the overall physiological relevance of the AT2receptor in the brain must also consider the Ang IV/AT4receptor.

Blockade of Renin Angiotensin System Ameliorates the Cardiac Arrhythmias and Sympathetic Neural Remodeling in Hearts of Type 2 DM Rat Model

2020 ◽  
Vol 20 (3) ◽  
pp. 464-478 ◽  
Author(s):  
Yomna M. Yehya ◽  
Abdelaziz M. Hussein ◽  
Khaled Ezam ◽  
Elsayed A. Eid ◽  
Eman M. Ibrahim ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cardiac Arrhythmias ◽  
Sympathetic Nerve ◽  
Renin Angiotensin System ◽  
Diabetic Rats ◽  
Angiotensin System ◽  
Type 2 Dm ◽  
Type 2 Diabetic ◽  
Diabetes Induction

Objectives:: The present study was designed to investigate the effects of renin angiotensin system (RAS) blockade on cardiac arrhythmias and sympathetic nerve remodelling in heart tissues of type 2 diabetic rats. Methods:: Thirty-two male Sprague Dawley rats were randomly allocated into 4 equal groups; a) normal control group: normal rats, b) DM group; after type 2 diabetes induction, rats received 2ml oral saline daily for 4 weeks, c) DM+ ACEi: after type 2 diabetes induction, rats were treated with enalapril (10 mg/kg, orally for 4 weeks) and d) DM+ ARBs: after type 2 diabetes induction, rats were treated with losartan (30 mg/kg, orally for 4 weeks). Results:: In type 2 diabetic rats, the results demonstrated significant prolongation in Q-T interval and elevation of blood sugar, HOMA-IR index, TC, TGs, LDL, serum CK-MB, myocardial damage, myocardial MDA, myocardial norepinephrine and tyrosine hydroxylase (TH) density with significant reduction in serum HDL, serum insulin and myocardial GSH and CAT. On the other hand, blockade of RAS at the level of either ACE by enalapril or angiotensin (Ag) receptors by losartan resulted in significant improvement in ECG parameters (Q-T), cardiac enzymes (CK-MB), cardiac morphology, myocardial oxidative stress (low MDA, high CAT and GSH) and myocardial TH density. Conclusions:: RAS plays a role in the cardiac sympathetic nerve sprouting and cardiac arrhythmias induced by type 2 DM and its blockade might have a cardioprotective effect via attenuation of sympathetic nerve fibres remodelling, myocardial norepinephrine contents and oxidative stress.

Therapeutic potential of renin angiotensin system inhibitors in cancer cells metastasis

2020 ◽  
Vol 216 (7) ◽  
pp. 153010 ◽  
Author(s):  
Milad Hashemzehi ◽  
Farimah Beheshti ◽  
Seyed Mahdi Hassanian ◽  
Gordon A. Ferns ◽  
Majid Khazaei ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Therapeutic Potential ◽  
Renin Angiotensin System ◽  
Angiotensin System ◽  
Renin Angiotensin

scholarly journals Divergent mechanism regulating fluid intake and metabolism by the brain renin-angiotensin system

2012 ◽  
Vol 302 (3) ◽  
pp. R313-R320 ◽  
Author(s):  
Curt D. Sigmund
Keyword(s):  
Blood Pressure ◽  
Fluid Intake ◽  
Renin Angiotensin System ◽  
Metabolic Effects ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Intracellular Form ◽  
Efferent Pathways ◽  
The Brain ◽  
Pituitary Adrenal Axis

The purpose of this review is two-fold. First, I will highlight recent advances in our understanding of the mechanisms regulating angiotensin II (ANG II) synthesis in the brain, focusing on evidence that renin is expressed in the brain and is expressed in two forms: a secreted form, which may catalyze extracellular ANG I generation from glial or neuronal angiotensinogen (AGT), and an intracellular form, which may generate intracellular ANG in neurons that may act as a neurotransmitter. Second, I will discuss recent studies that advance the concept that the renin-angiotensin system (RAS) in the brain not only is a potent regulator of blood pressure and fluid intake but may also regulate metabolism. The efferent pathways regulating the blood pressure/dipsogenic effects and the metabolic effects of elevated central RAS activity appear different, with the former being dependent upon the hypothalamic-pituitary-adrenal axis, and the latter being dependent upon an interaction between the brain and the systemic (or adipose) RAS.

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