Abstract
Pharmacological research in mice and human genetic analyses suggest that the kallikrein-kinin system (KKS) may regulate anxiety. We examined the role of the KKS in anxiety and stress in both species. In human genetic association analysis, variants in genes for the bradykinin precursor (KNG1) and the bradykinin receptors (BDKRB1 and BDKRB2) were associated with anxiety disorders (p < 0.05). In mice, however, neither acute nor chronic stress affected B1 receptor gene or protein expression, and B1 receptor antagonists had no effect on anxiety tests measuring approach-avoidance conflict. We thus focused on the B2 receptor and found that mice injected with the B2 antagonist WIN 64338 had lowered levels of a physiological anxiety measure, the stress-induced hyperthermia (SIH), vs controls. In the brown adipose tissue, a major thermoregulator, WIN 64338 increased expression of the mitochondrial regulator Pgc1a and the bradykinin precursor gene Kng2 was upregulated after cold stress. Our data suggests that the bradykinin system modulates a variety of stress responses through B2 receptor-mediated effects, but systemic antagonists of the B2 receptor were not anxiolytic in mice. Genetic variants in the bradykinin receptor genes may predispose to anxiety disorders in humans by affecting their function.
Highlights
Pharmacological research in mice and human genetic analyses suggest that the kallikrein-kinin system (KKS) may regulate anxiety
To investigate whether genetic variants in the KKS genes associate with anxiety disorders, we genotyped SNPs from KNG1, bradykinin receptor B1 (BDKRB1), and bradykinin receptor B2 (BDKRB2) in anxiety disorder cases (n = 321) and carefully matched controls (n = 653) from the Finnish population-based Health 2000 Survey
We used multiple approaches to investigate whether the KKS regulates stress-related phenotypes and anxiety disorders
Summary
Pharmacological research in mice and human genetic analyses suggest that the kallikrein-kinin system (KKS) may regulate anxiety. In human genetic association analysis, variants in genes for the bradykinin precursor (KNG1) and the bradykinin receptors (BDKRB1 and BDKRB2) were associated with anxiety disorders (p < 0.05). Genetic variants in the bradykinin receptor genes may predispose to anxiety disorders in humans by affecting their function. A functional genetic variant within the promoter region of BDKRB2 has been associated with panic disorder in a candidate gene study of 306 modulators of neurotransmitter systems[6]. In patients with posttraumatic stress disorder (PTSD), variants in ACE associate both with the severity of PTSD symptoms, and the effectiveness of ACE inhibitors to attenuate them[8] It is not known, whether this effect is mediated by the KKS. How these bradykinin-related changes in corticosterone levels are related to stress-associated behaviours, such as anxiety, is not known
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