Berger, Thilo
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Kinetics and interrelations of the renin aldosterone response to acute psychosocial stress : a neglected stress system
Context:
The Renin-Angiotensin-Aldosterone-System (RAAS) plays an important role in cardiovascular homeostasis and its dysfunction relates to negative health consequences. Acute psychosocial stress seems to activate the RAAS in humans, but stress kinetics and interrelations of RAAS parameters as compared to a non-stress control group remain inconclusive.
Objective:
We systematically investigated in a randomized placebo-controlled design stress kinetics and interrelations of the reactivity of RAAS parameters measured in plasma and saliva to standardized acute psychosocial stress induction.
Methods:
58 healthy young men were assigned to either a stress or a placebo-control group. The stress group underwent the Trier-Social-Stress-Test (TSST), while the control group underwent the placebo-TSST. We repeatedly assessed plasma renin, plasma and salivary aldosterone, before, and up to 3h after stress/placebo. We simultaneously assessed salivary cortisol to validate successful stress induction and to test for interrelations.
Results:
Acute psychosocial stress induced significant increases in all endocrine measures as compared to placebo-stress (p´s≤.041). Highest renin levels were observed 1min after stress, highest aldosterone and cortisol levels 10 and 20min after stress, with salivary aldosterone starting earlier at 1min after stress. Renin completed recovery at 10min, cortisol at 60min, salivary aldosterone at 90min, and plasma aldosterone at 180min after stress. Stress increase scores of all endocrine measures related to each other, as did renin and cortisol AUCi´s and salivary and plasma aldosterone AUCi´s (p´s≤.047).
Conclusions:
Our findings suggest that in humans acute psychosocial stress induces a differential and interrelated RAAS parameter activation pattern. Potential implications for stress-related cardiovascular risk remain to be elucidated.
Immunoproteasome Inhibition Impairs T and B Cell Activation by Restraining ERK Signaling and Proteostasis
Immunoproteasome (IP) inhibition holds potential as a novel treatment option for various immune-mediated pathologies. The IP inhibitor ONX 0914 reduced T cell cytokine secretion and Th17 polarization and showed pre-clinical efficacy in a range of autoimmune disorders, transplant-allograft rejection, virus-mediated tissue damage, and colon cancer progression. However, the molecular basis of these effects has remained largely elusive. Here, we have analyzed the effects of ONX 0914 in primary human and mouse lymphocytes. ONX 0914-treatment impaired primary T cell activation in vitro and in vivo. IP inhibition reduced ERK-phosphorylation sustainment, while leaving NF-κB and other signaling pathways unaffected. Naïve T and B cells expressed nearly exclusively immuno- or mixed proteasomes but no standard proteasomes and IP inhibition but not IP-deficiency induced mild proteostasis stress, reduced DUSP5 expression and enhanced DUSP6 protein levels due to impaired degradation. However, accumulation of DUSP6 did not cause the reduced ERK-phosphorylation in a non-redundant manner. We show that broad-spectrum proteasome inhibition and immunoproteasome inhibition have distinct effects on T cell activation at the molecular level. Notably, ONX 0914-treated T cells recovered from proteostasis stress without apoptosis induction, apparently via Nrf1-mediated up-regulation of standard proteasomes. In contrast, B cells were more susceptible to apoptosis after ONX 0914-treatment. Our data thus provide mechanistic insights how IP inhibition functionally impedes T and B cells likely accounting for its therapeutic benefits.