Mas receptor knockout mice exposed to chronic unpredictable stress exhibited 30% higher plasma corticosterone (364 vs 280 ng/ml, p<0.0001) and enhanced depression-like and anxiety-like behaviors compared to wild-type controls.
Does genetic deletion of the Mas receptor exacerbate neuroendocrine and behavioral responses to chronic unpredictable stress in mice?
Genetic deletion of the Mas receptor exacerbates HPA axis hyperactivation, anxiety- and depression-like behaviors, and BDNF reduction in response to chronic stress, highlighting the neuroprotective role of the Ang-(1-7)/Mas axis.
Effect estimate: p<0.0001, Cohen’s d=1.35 for corticosterone levels higher in Mas KO vs WT under CUS
Absolute Event Rate: 364% vs 280%
p-value: p=<0.0001
Abstract Stress is defined as a disruption of homeostasis that elicits adaptive responses aimed at restoring physiological balance. However, when stress becomes chronic or overwhelming, maladaptive changes may occur, contributing to endocrine, behavioral, and neuropsychiatric dysfunctions. Beyond the classical neuroendocrine axes, such as the sympatho-adrenomedullary and hypothalamic–pituitary–adrenal (HPA) axes, the renin-angiotensin system has also being implicated in stress modulation. Previous studies have shown that angiotensin-(1–7), acting through its receptor Mas, exerts a modulatory effect on the stress response, attenuating anxiety- and depression-like behaviors induced by various stressors. Here we investigated the impact of genetic deletion of Mas on the consequences of chronic unpredictable stress (CUS) exposure. Over 21 consecutive days, mice were subjected to random stressors, after which endocrine, behavioral and neurochemical assessments were performed. Mas knockout (KO) mice exposed to CUS exhibited significantly elevated corticosterone and blood glucose levels compared to stressed wild-type mice. In behavioral tests, stressed Mas KO mice displayed the highest immobility times in the forced swimming test, indicating enhanced depressive-like behavior. Anxiety-like behavior was also heightened in Mas KO mice, as evidenced by a significant reduction in the percentage of time spent in the open arms of the elevated plus maze test. Neurochemical analysis revealed a marked reduction in brain-derived neurotrophic factor (BDNF) levels in key brain regions of stressed Mas KO animals. Together, these findings suggest that Mas plays a critical role in the neurobiology of stress, since its absence exacerbates HPA axis hyperactivity, depression- and anxiety-like behaviors, as well as BDNF reduction. Overall, these results highlight the potential neuroprotective role of Mas in stress-related disorders.
Gonçalves et al. (Thu,) conducted a other in Adult male Mas receptor knockout mice and wild-type controls aged 8-12 weeks exposed to chronic unpredictable stress or control conditions (n=32). Genetic deletion of Mas receptor (Mas knockout) with chronic unpredictable stress (CUS) exposure vs. Wild-type mice with and without chronic unpredictable stress exposure was evaluated on Plasma corticosterone levels, fasting blood glucose, depression-like behavior (immobility in forced swimming test and tail suspension test), anxiety-like behavior (time spent in open arms of elevated plus maze), and BDNF levels in brain regions after CUS (p<0.0001, Cohen’s d=1.35 for corticosterone levels higher in Mas KO vs WT under CUS, p=<0.0001). Mas receptor knockout mice exposed to chronic unpredictable stress exhibited 30% higher plasma corticosterone (364 vs 280 ng/ml, p<0.0001) and enhanced depression-like and anxiety-like behaviors compared to wild-type controls.