Mineralocorticoid receptor associates with pro‐inflammatory bias in the hippocampus of spontaneously hypertensive rats

Abstract

Damage observed in the hippocampus of the adult spontaneously hypertensive rat (SHR) resembles the neuropathology of mineralocorticoid-induced hypertension, supporting a similar endocrine dysfunction in both entities. In the present study, we tested the hypothesis that increased expression of the hippocampal mineralocorticoid receptor (MR) in SHR animals is associated with a prevalent expression of pro-inflammatory over anti-inflammatory factors. Accordingly, in the hippocampus, we measured mRNA expression and immunoreactivity of the MR and glucocorticoid receptor (GR) using a quantitative polymerase chain reaction and histochemistry. We also measured serum-glucocorticoid-activated kinase 1 (Sgk1 mRNA), the number and phenotype of Iba1+ microglia, as well as mRNA expression levels of the pro-inflammatory factors cyclo-oxygenase 2 (Cox2), Nlrp3 inflammasome and tumour necrosis factor α (Tnfα). Expression of anti-inflammatory transforming growth factor (Tgf)β mRNA and the NADPH-diaphorase activity of nitric oxide synthase (NOS) were also determined. The results showed that, in the hippocampus of SHR rats, expression of MR and the number of immunoreactive MR/GR co-expressing cells were increased compared to Wistar-Kyoto control animals. Expression of Sgk1, Cox2, Nlrp3 and the number of ramified glia cells positive for Iba1+ were also increased, whereas Tgfβ mRNA expression and the NADPH-diaphorase activity of NOS were decreased. We propose that, in the SHR hippocampus, increased MR expression causes a bias towards a pro-inflammatory phenotype characteristic for hypertensive encephalopathy.

Top‐down and bottom‐up control of stress‐coping

“…71 Processes under the control of MR promote the initial phase of the stress reaction. 72 When the stress response proceeds, circulating glucocorticoid concentrations rise and the hormone starts, via GR, to prevent these initial defence reactions from overshooting and becoming damaging. 73 At the same time, this later GR-mediated action promotes memory consolidation of the experience.…”

“…63,64 In hippocampal CA1 pyramidal neurones, MR-induced excitability is suppressed and normalised by a genomic GR-mediated action and these opposing actions provide a U-shaped dose-response curve to corticosterone. 72 When the stress response proceeds, circulating glucocorticoid concentrations rise and the hormone starts, via GR, to prevent these initial defence reactions from overshooting and becoming damaging. Membrane MR-and genomic GR-mediated actions can cooperate and promote metaplasticity of basolateral amygdala neurones 67 ; this implies that excitability is rapidly increased via the membrane MR and subsequently maintained upon activation of the genomic GR.…”

Vitamin D receptor activation regulates microglia polarization and oxidative stress in spontaneously hypertensive rats and angiotensin II-exposed microglial cells: Role of renin-angiotensin system

“…However, as a newly identified heptapeptide of RAS, angiotensin-(1–7) (Ang-(1–7)), catalyzed by ACE2 from Ang II, is protective against inflammation and oxidative damage through binding with MasR, counteracting the deleterious effects of ACE/Ang II/AT1 pathway [4]. The spontaneously hypertensive rat (SHR), a widely used animal model of hypertension, exhibits neurological dysfunction, neuroimmune activation and oxidative brain damage [[5], [6], [7]]. The overactivated ACE/AngII/AT1 signaling but weakened ACE2/Ang(1–7)/MasR signaling also has been observed in the brain tissues of SHR, raising the possibility that rebalancing the RAS system might be neuroprotective [8].…”

Mineralocorticoid receptor antagonist‐mediated cognitive improvement in a mouse model of Alzheimer's type: possible involvement of BDNF‐H2S‐Nrf2 signaling

“…In contrast, the present study showed the improvement of learning and memory in response to repeated administration of mineralocorticoid receptor blockers in Aβ 1‐42 ‐treated mice. It is reported that the chronic blockade of mineralocorticoid receptors prevents neurodegenerative pro‐inflammatory cascade in the hippocampus [50], which is one of the most important pathogenic mechanisms involved in Aβ 1‐42 ‐induced cognitive deterioration [51]. Accordingly, it is possible to suggest that repeated administration of mineralocorticoid receptor may attenuate Aβ 1‐42 ‐induced neuroinflammation to prevent cognitive decline in an experimental model of dementia.…”