Renin-angiotensin system: The underlying mechanisms and promising therapeutical target for depression and anxiety

Abstract

Emotional disorders, including depression and anxiety, contribute considerably to morbidity across the world. Depression is a serious condition and is projected to be the top contributor to the global burden of disease by 2030. The role of the renin-angiotensin system (RAS) in hypertension and emotional disorders is well established. Evidence points to an association between elevated RAS activity and depression and anxiety, partly through the induction of neuroinflammation, stress, and oxidative stress. Therefore, blocking the RAS provides a theoretical basis for future treatment of anxiety and depression. The evidence for the positive effects of RAS blockers on depression and anxiety is reviewed, aiming to provide a promising target for novel anxiolytic and antidepressant medications and/or for improving the efficacy of currently available medications used for the treatment of anxiety and depression, which independent of blood pressure management.

Keywords: angiotensin II; anxiety; deprssion; neuroinflammation; renin-angiotensin system.

Figure 1

(A) The overview of RAS and the role of the RAS in the pathophysiology of anxiety and depression. Notes: The blue dashed line pointed to the positive effects, such as antidepressant-like and anxiolytic effects. Two key regulatory pathways: the classical axis ACE/Ang II/AT1 receptor pathway and the non-classical pathway ACE2/Ang-(1–7)/Mas receptor pathway. Under physiological conditions, the two pathways regulated each other and maintained a dynamic balance. Ang II aggravated oxidative stress and inflammation response by activating AT1R to upregulate the ACE/Ang II/AT1R pathway, promoting the development of emotional disorders. Ang II activated non-classical pathways by activating AT2R and MasR, producing antidepressant-like and anxiolytic effects. Thus, the beneficial effects of RAS blockers may be due to inhibiting oxidative stress and inflammation by directly targeting Ang II and its AT1 receptor. Other potential targets of anxiolytic drugs include renin, ACE2, AT2 receptors, and Mas receptors. (B) RAS and oxidative stress in depression and anxiety Notes: The pro-inflammatory effects of Ang II were largely mediated by increased oxidative stress. During inflammation, Ang II activated AT₁R to promote the oxidative stress process by increasing NADPH oxidase and iNOS activity in the BBB and PVN, resulting in an accumulation of ROS and NO and ultimately aggravating emotional disorders. Antioxidant enzyme activity was decreased during oxidative stress, which was prevented by RAS blockers and antioxidants. Furthermore, Ang II directly increased ROS generation and triggered lipid peroxidation, inhibited by RAS inhibitors and antioxidants. (C) HPA and RAS. Notes: The type of stress caused HPA axis activation and increased the downstream hormones such as CRH, ACTH, and GC, eventually promoting anxiety and depression. Stress increased Ang II levels, which in turn raised the expression of CRH mRNA, induced the release of ACTH and GC, and enhanced the stimulatory effects of CRH through AT1R located in the pituitary and PVN. The absence of AT2 receptor transcription enhanced the AT1 receptor expression in brain areas and was involved in regulating the HPA axis, which was associated with anxiety and depression. Pretreatment with RAS blockers attenuated neuroendocrine responses, preventing the development of stress-induced anxiety/depression-like behaviors. (C) RAS and oxidative stress in depression and anxiety. Notes: The pro-inflammatory effects of Ang II were largely mediated by increased oxidative stress. During inflammation, Ang II activated AT₁R to promote the oxidative stress process by increasing NADPH oxidase and iNOS activity in the BBB and PVN, resulting in an accumulation of ROS and NO and ultimately aggravating emotional disorders. Antioxidant enzyme activity was decreased during oxidative stress, which was prevented by RAS blockers and antioxidants. Furthermore, Ang II directly increased ROS generation and triggered lipid peroxidation, inhibited by RAS inhibitors and antioxidants.