New research now details the interplay between proteins involved in controlling the body’s stress response and points to potential therapeutic targets when this response goes awry. The study, which was conducted by an international team led by investigators at McLean Hospital, appears in the journal Cell Reports.
“A dysregulated stress response of the body can be damaging for the brain and promote susceptibility to mood and anxiety disorders,” said lead author Jakob Hartmann, Ph.D.. Hartmann is an assistant neuroscientist in the Neurobiology of Fear Laboratory at McLean and an instructor in psychiatry at Harvard Medical School.
“A key brain region involved in the regulation of the stress response is the hippocampus,” said Hartmann. “The idea for this study occurred to us when we noticed interesting distinctions in hippocampal localization of three important stress-regulating proteins.”
The researchers’ experiments in non-human tissue and postmortem brain tissue revealed how these proteins—the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), and the FK506-binding protein 51 (FKBP5)—interact with each other.
Specifically, MRs, rather than GRs, control the production of FKBP5 under normal conditions. FKBP5 decreases GRs’ sensitivity to binding stress hormones during stressful situations. FKBP5 appears to fine-tune the stress response by acting as a mediator of the MR:GR balance in the hippocampus.
“Our findings suggest that therapeutic targeting of GR, MR, and FKBP5 may be complementary in manipulating central and peripheral regulation of stress,” said senior author Kerry J. Ressler, MD, Ph.D.. Ressler is the chief scientific officer at McLean Hospital, chief of McLean’s Division of Depression and Anxiety Disorders, and a professor in psychiatry at Harvard Medical School.
“Moreover, our data further underline the important but largely unappreciated role of MR signaling in stress-related psychiatric disorders,” added Ressler. “The findings of this study will open new directions for future research.”
The important contribution of an activated sympathetic nervous system (SNS) to hypertension is well established (Esler, 1995, 2015). However, a clear demonstration of the neurogenic contribution to angiotensin (Ang) dependent hypertension has been complicated by the direct vasoconstrictor actions of systemically administered Ang II on vascular and cardiac structure which influence neuroeffector function, and by chronic baroreflex suppression of the SNS (Moretti et al., 2009).
To avoid the constrictor complications, an alternative approach is to use a low systemic dose of Ang II that does not elicit an immediate pressor response but that increases blood pressure in the long term in part via a centrally mediated increase in neurogenic vasomotor tone (Cox and Bishop, 1991).
We developed a model of low level activation of the renin-angiotensin-aldosterone system (RAAS) in rabbits which involves a 12 week systemic infusion of a very low dose of Ang II producing only a modest increase in blood pressure but a substantial increase in renal sympathetic activity (RSNA; Moretti et al., 2012).
The brain regions first activated by low dose Ang II, demonstrated using Fos related antigen, are the circumventricular organs such as the subfornical organ (SFO) and organum vasculosum lamina terminalis (OVLT). This is due to the lack of blood brain barrier and high density of AT1 receptors (AT1R) in this region. However, the initial activity diminishes over time, possibly due to down-regulation of the AT1R (Davern and Head, 2007).
Our data further show that four brain regions remain activated after 12 weeks of Ang II infusion: the OVLT, median preoptic nucleus, supraoptic nucleus (SON), and paraventricular nucleus (PVN). However, only the PVN showed a sustained activation of Fos that paralleled the sustained sympathetic activation (Moretti et al., 2012) and may therefore be the region driving the sympatho-excitation in the long term. Indeed, there is considerable evidence that circulating Ang II activates AT1R in the SFO which project to the PVN, inducing reactive oxygen species and increased expression of p47phox and gp91phox (Oliveira-Sales et al., 2009).
Ang II may also directly activate AT1R in the PVN due to a breakdown of the blood brain barrier in subjects with hypertension. PVN neurons project to pre-sympathetic neurons in the spinal cord (Saper et al., 1976) and are prime candidates to mediate the sympatho-excitation observed with Ang II hypertension (Biancardi et al., 2014). This view is supported by studies showing knock down of AT1R only in the PVN prevents most of the increase in blood pressure (Chen A. et al., 2014).
There is evidence that in addition to AT1R activation in the PVN, mineralocorticoid receptors (MR) in this region may also be involved in promoting Ang II-induced hypertension. Elevated Ang II levels by exogenous infusion or stimulation of renin increase serum aldosterone levels through modulation of adrenal production.
MR activation by aldosterone is central for sodium and water homeostasis in the kidney epithelial cells, but MR are expressed in many non-epithelial cell types including the brain (Oki et al., 2012; Chen J. et al., 2014; Joels and de Kloet, 2017). Of note, the MR are only activated by aldosterone in a limited number of tissues. This is due to the intrinsic equivalent affinity of the MR for both aldosterone and cortisol.
Co-expression of a hydroxy steroid dehydrogenase type II enzyme (11bHSD2) metabolizes cortisol and prevents its access to the MR; this is well described in renal epithelial cells for the control of sodium and potassium homeostasis (Krozowski et al., 1995). MR that are not colocalized with 11bHSD2 respond to cortisol under normal physiological conditions, particularly in the brain (Iqbal et al., 2014; Joels and de Kloet, 2017). Moreover, in peripheral cells in the presence of cell stress the MR responds to cortisol as an agonist equivalent to aldosterone, suggesting a range of signaling outcomes for cortisol-bound MR (Ward et al., 2001).
While 11bHSD2 is widely expressed in the developing brain, it is only found in a small number of regions in the adult brain including the nucleus tractus solatarii (NTS) and the PVN. These regions are proposed to respond to aldosterone for the control of salt appetite and thirst (Geerling and Loewy, 2007; Oki et al., 2012; Chen J. et al., 2014; Haque et al., 2015). Intracerebroventricular (ICV) infusion of the MR antagonist RU28318 can reduce the blood pressure rise to systemic Ang II and other pressor agents such as aldosterone (Xue et al., 2011).
Further, central infusion of an aldosterone synthase inhibitor (FAD286) or MR antagonist (spironolactone) prevented most of the Ang II-induced neuronal activation in the PVN and importantly the increase in blood pressure (Huang et al., 2010). By contrast, Fos in the SON was not altered, confirming the importance of the MR and potentially aldosterone in the PVN rather than the SON for modifying Ang II-induced hypertension.
The question therefore is whether AT1R signaling with or without combined MR/aldosterone signaling in the PVN mediates the sympatho-excitation during low Ang II-mediated hypertension. To the best of our knowledge, no previous study has injected the antagonists directly into the PVN.
Thus, the aims of the present study were to determine, in conscious rabbits (1) whether low level activation of the RAAS modeled by infusion of a low dose of Ang II for 12 weeks causes sustained activation of neurons in the PVN resulting in amplified sympathetic and pressor responses to stress, chemoreceptor activation and ultimately hypertension and (2) whether the process involves increased MR and/or AT1R activation in the PVN.
Our approach was to deliver antagonists directly into the PVN in conscious rabbits and to test sympathetic responses to stimulation of chemoreceptor and stress pathways and to also examine the baroreflex. We blocked MR using the highly specific antagonist RU28318 (Young et al., 1995) and AT1R using losartan (Mayorov and Head, 2003). To determine the overall contribution of the PVN, we examined the effect of muscimol (Maiorov et al., 2000) as it provides neuronal inhibition via activation of GABAA receptors.
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982587/
More information: Jakob Hartmann et al, Mineralocorticoid receptors dampen glucocorticoid receptor sensitivity to stress via regulation of FKBP5, Cell Reports (2021). DOI: 10.1016/j.celrep.2021.109185