Renin-Angiotensin System Interactions in Stress and Mood Disorders

The renin–angiotensin system (RAS) is traditionally recognised for its regulation of blood pressure and fluid balance, but mounting evidence highlights its multifaceted role in the central nervous system, particularly in the modulation of stress responses and emotional regulation. Components of RAS, including angiotensin-converting enzyme (ACE), angiotensin II (Ang II) and its receptors (AT1 and AT2), are widely expressed in brain regions implicated in mood control, such as the hippocampus, prefrontal cortex and amygdala. Elevated RAS signalling can promote neuroinflammation, oxidative stress and dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, all of which are established contributors to anxiety and depression. Conversely, blockade of classical RAS pathways through ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) exerts neuroprotective and anti-inflammatory effects, enhances neurotrophic support (including brain-derived neurotrophic factor, BDNF) and normalises HPA axis activity. Preclinical models demonstrate that chronic Ang II exposure induces depressive-like behaviour via microglial activation and cytokine release, while RAS antagonists confer resilience to chronic stress and improve cognitive and affective outcomes. Clinically, repurposing antihypertensive agents offers a promising strategy to augment current treatments for mood disorders, with potential to reduce disease burden in both psychiatric and cardiovascular comorbid populations.

Research from Nature Portfolio

Recent studies have directly manipulated central RAS tone to uncover causal links with depressive phenotypes. In a murine model, chronic subcutaneous infusion of Ang II led to sustained microglial activation in the hippocampus, upregulation of proinflammatory cytokines and HPA axis hyperactivation, culminating in pronounced behavioural despair; co-treatment with an AT1 antagonist or microglial inhibitor effectively reversed both molecular and behavioural alterations. Another investigation using a rat model of unpredictable chronic mild stress revealed that dietary or pharmacological interventions targeting RAS-associated oxidative and inflammatory pathways could restore hippocampal BDNF levels, reduce lipid peroxidation and rescue stress-induced memory impairments, thereby illustrating the broader interplay between RAS, neurotrophic support and cognitive-emotional resilience.

Renin-Angiotensin System Interactions in Stress and Mood Disorders publication trend

The graph below shows the total number of articles in renin-angiotensin system interactions in stress and mood disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Renin–Angiotensin System (RAS): A hormone cascade that generates angiotensin II to regulate vascular tone, electrolyte balance and central nervous system functions.

Angiotensin II (Ang II): A bioactive peptide that binds AT1 and AT2 receptors, mediating vasoconstriction, inflammation and neuromodulatory effects.

Angiotensin-Converting Enzyme Inhibitors (ACEIs): Drugs that block the conversion of angiotensin I to angiotensin II, reducing RAS activity.

Angiotensin Receptor Blockers (ARBs): Agents that selectively antagonise AT1 receptors, attenuating inflammatory and stress-related pathways.

Hypothalamic–Pituitary–Adrenal (HPA) Axis: The major neuroendocrine system controlling stress hormone release, often dysregulated in mood disorders.

Microglia: Resident immune cells of the brain that, when activated, release cytokines contributing to neuroinflammation.

Brain-Derived Neurotrophic Factor (BDNF): A growth factor crucial for neuronal survival, synaptic plasticity and mood regulation.

References

1. Renin-angiotensin system: The underlying mechanisms and promising therapeutical target for depression and anxiety. Frontiers in Immunology (2023).
2. Role of brain renin–angiotensin system in depression: A new perspective. CNS Neuroscience & Therapeutics (2023).
3. Antidepressant-like effect of losartan involves TRKB transactivation from angiotensin receptor type 2 (AGTR2) and recruitment of FYN. Neuropharmacology (2018).
4. Candesartan prevents impairment of recall caused by repeated stress in rats. Psychopharmacology (2012).
5. Chronically infused angiotensin II induces depressive-like behavior via microglia activation. Scientific Reports (2020).
6. Vitamin D3 administration prevents memory deficit and alteration of biochemical parameters induced by unpredictable chronic mild stress in rats. Scientific Reports (2021).