Downregulation of glucocorticoid receptors on hypothalamic CRH neurons contributes to primary hypertension

The corticotropin-releasing hormone (CRH) is a neuropeptide synthesized by CRH neurons in brain regions including paraventricular nucleus (PVN) of the hypothalamus. The glucocorticoids synthesized and released by the adrenal glands inhibit CRH production in PVN-CRH neurons, thereby negatively regulating glucocorticoid levels. The glucocorticoid receptors (GRs) on PVN-CRH neurons are critical in mediating this negative feedback regulating CRH synthesis and release. Primary hypertension is associated with increased CRH mRNA levels and enhanced stress response. The number of CRH-expression neurons are significantly increased in PVN in primary hypertension patients. This study determined if GRs on PVN-CRH neurons is altered in a rat model of primary hypertension, and this alteration contributes to the elevated sympathetic outflow in hypertension. We found that the GRs mRNA and protein level in the PVN was significantly lower in adult spontaneously hypertensive rats (SHRs) than in age-matched Wistar-Kyoto rats (WKYs), while the mineralocorticoid receptors (MRs) gene expression did not differ between WKY rats and SHRs. Immunostaining showed that GRs immunoreactivities were expressed mainly in PVN-CRH neurons, but not autonomic neurons identified by retrograde tracer injected into the rostral ventrolateral medulla (RVLM). The number of GR-positive CRH neurons were profoundly fewer in SHRs than in WKY rats. Furthermore, the plasma norepinephrine level is significant higher in SHRs than in WKY rats. Microinjection of the GRs antagonist mifepristone (3 ng in 100 nl/side) into the PVN significantly increased blood pressure (BP), renal sympathetic nerve activity (RSNA) and heart rate (HR) in anesthetized WKY rats but did not change BP, RSNA, and HR in SHRs. Pretreatment of brain slice WKY rats with mifepristone (20 μM) for 1 hr significantly increased firing activities of PVN-CRH neurons and PVN-RVLM neurons. Whereas the frequency of both spontaneous excitatory postsynaptic synaptic currents (EPSCs) and inhibitory postsynaptic synaptic currents (IPSCs) did not change in response to mifepristone incubation. On the contrary, activating of GRs by microinjection of the specific agonist fluticasone propionate (FP, 3 ng, 100 nl/side) into the PVN did not change BP, RSNA, and HR in anesthetized SHRs. Pretreatment of brain slice SHRs with FP (10 μM) did not change the firing activities, EPSCs, or IPSCs in PVN-CRH neurons and PVN-RVLM neurons. Overexpression of GRs on PVN-CRH neurons guided by the CRH-Cre decreased BP in conscious SHRs, plasma norepinephrine levels, and the firing activities in PVN-CRH neurons. These data suggest that a downregulation of GRs in PVN-CRH neurons is involved in the hyperactivity of PVN-CRH neurons and increased sympathetic outflow in SHRs. Restoration of GRs expression in PVN-CRH neurons may lead to developing novel approaches to treat hypertension. National Institutes of Health (HL159157) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.