Deletion of RGS2 Results in Increased Blood Pressure and Depression-Like Behavior in the Presence of Elevated Ang II Levels in Female Mice.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology(2022)
Abstract
Hypertension and depression are major health problems in the US. Overactivity of the renin angiotensin system (RAS) plays an important role in the pathophysiology of hypertension and depression. The actions of the main effector peptide of the RAS, angiotensin II (Ang II), are mediated by the Ang II type 1 receptor whose activity is modulated by regulator of G-protein signaling (RGS) proteins, including RGS2. In this study, we assessed the effects of genetic deletion of RGS2 on Ang II-induced increases in blood pressure (using tail cuff plethysmography) and depression-like behavior (using the tail suspension test) in adult male and female mice. Adult male and female RGS2 wild-type (RGS2 ) and RGS2-deficient (RGS2 ) mice were treated with osmotic minipumps containing either vehicle (saline) or Ang II (1 mg/kg/d) for 21 days. In males, baseline SBP was lower in RGS2 (SBP = 103±5 mmHg, n=14) vs RGS2 (SBP = 120±6 mmHg, n=13, P<0.05 vs RGS2 ) mice. By contrast, in females there was no difference in baseline SBP between RGS2 and RGS2 mice, suggesting that deletion of RGS2 results in lower baseline SBP in females only. Chronic treatment with Ang II increased SBP in both RGS2 and RGS2 mice compared to saline controls, irrespective of sex. There was no difference in Ang II-induced increases in SBP in RGS2 and RGS2 male mice, suggesting that RGS2 does not protect against Ang II-induced increases in SBP in male mice. By contrast, in female mice, Ang II-induced increases in SBP were greater in RGS2 compared to RGS2 mice (for example, after 21 days of Ang II treatment, change in SBP from baseline in RGS2 mice was 47±11 mmHg, n=5, and in RGS2 mice it was 73±15 mmHg n=4, P<0.05) suggesting that RGS2 protects against Ang II-induced increases in SBP in female, but not male mice. Chronic Ang II treatment also resulted in decreased immobilization time in RGS2 female mice, but not RGS2 mice compared to respective saline controls (immobilization time in vehicle-treated RGS2 = 187±14 sec, n=5; Ang II-treated RGS2 = 124±27 sec, n=5, P<0.05 vs vehicle-treated RGS2 ; vehicle-treated RGS2 = 196±16 sec, n=5; Ang II-treated RGS2 = 192±13 sec, n=4, P<0.05 vs Ang II-treated RGS2 ). These data suggest that RGS2 protects against depression-like behavior in the presence of elevated Ang II levels in female mice. In contrast to female mice, Ang II treatment and RGS2 deficiency had no effect on depression-like behavior in adult male mice. Overall, these data suggest that RGS2 protects against blood pressure increases and depression-like behavior after exposure to elevated Ang II levels in female mice, suggesting that RGS2 activation is a promising therapeutic target to treat elevated blood pressure and depression during conditions of elevated Ang II levels in females.
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Key words
elevated ang ii levels,rgs2 results,depression‐like,blood pressure
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