Expression of mineralocorticoid and glucocorticoid receptors in preautonomic neurons of the rat paraventricular nucleus

Abstract

Activation of mineralocorticoid receptors (MR) of the hypothalamic paraventricular nucleus (PVN) increases sympathetic excitation. To determine whether MR and glucocorticoid receptors (GR) are expressed in preautonomic neurons of the PVN and how they relate to endogenous aldosterone levels in healthy rats, retrograde tracer was injected into the intermediolateral cell column at T4 to identify preautonomic neurons in the PVN. Expression of MR, GR, 11-␤ hydroxysteroid dehydrogenase1 and 2 (11␤-HSD1, 2), and hexose-6-phosphate dehydrogenase (H6PD) required for 11␤-HSD1 reductase activity was assessed by immunohistochemistry. RT-PCR and Western blot analysis were used to determine MR gene and protein expression. Most preautonomic neurons were in the caudal mediocellular region of PVN, and most expressed MR; none expressed GR. 11␤-HSD1, but not 11␤-HSD2 nor H6PD immunoreactivity, was detected in the PVN. In rats with chronic low or high sodium intakes, the low-sodium diet was associated with significantly higher plasma aldosterone, MR mRNA and protein expression, and c-Fos immunoreactivity within labeled preautonomic neurons. Plasma corticosterone and sodium and expression of tonicity-responsive enhancer binding protein in the PVN did not differ between groups, suggesting osmotic adaptation to the altered sodium intake. These results suggest that MR within preautonomic neurons in the PVN directly participate in the regulation of sympathetic nervous system drive, and aldosterone may be a relevant ligand for MR in preautonomic neurons of the PVN under physiological conditions. Dehydrogenase activity of 11␤-HSD1 occurs in the absence of H6PD, which regenerates NADP ϩ from NADPH and may increase MR gene expression under physiological conditions. mineralocorticoid receptor; aldosterone; sympathetic nervous system; preautonomic neuron; paraventricular nucleus; glucocorticoid receptor; 11-␤ hydroxysteroid dehydrogenase; sodium THE RENIN-ANGIOTENSIN-ALDOSTERONE system (RAAS) and sympathetic nervous system (SNS) interact to maintain fluid, electrolyte, and hemodynamic homeostasis essential for terrestrial life where sodium intake is often limited. Both the RAAS and SNS are activated by a lowering sodium intake, adaptive mechanisms ensuring adequate blood pressure (17,51,52,60,64,104). The paraventricular nucleus (PVN), and the SNS were shown by ablation studies to have a crucial role in mineralocorticoid-salt excess models of hypertension (6, 58). Chronic systemic aldosterone excess, as well as the intracerebroventricular infusion of aldosterone administered at concentrations too low to be effective when infused systemically, increase blood pressure and SNS activity (35,61). In both models, the hypertension and sympathetic activation are prevented by the intracerebroventricular infusion of mineralocorticoid receptor (MR) antagonists at doses lower than the effective dose infused peripherally (35,39,61). Xue et al. (108) reproduced these pharmacological results with the intracerebroventricular infusion of MR siRNA (108).The ...

The Multifaceted Mineralocorticoid Receptor

“…11β-HSD2 was not detected in the PVN, confirming several earlier reports. 11β-HSD1, but not H6PD, was coexpressed with MR in tracer-identified neurons, suggesting that aldosterone selectivity of MR in these neurons may be conferred by dehydrogenase activity of 11β-HSD1 (71). …”

“…Upon differentiation and expression of H6PD, 11β-HSD1 becomes a reductase (53). The expression of 11β-HSD1, but not H6PD, in preautonomic nerves of the PVN suggests that MR in these neurons may normally be regulated by endogenous aldosterone (71). …”

“…In the case of the granulosa cell, the predominance of one 11β-HSD over depends on the gonadotropin concentrations (437). In summary, the regulation of intracellular glucocorticoid concentrations by 11β-HSD1 and 11β-HSD2 is crucial for the regulation of both MR and GR activation in a variety of tissues and attention to the availability of cofactors must be considered when analyzing their activities (71, 127, 221, 304, 312, 425, 427, 439). …”

“…Levels of MR mRNA and protein were found to be increased in the PVN of rats on a chronically low, compared to high, sodium intake. Predictably, plasma aldosterone concentration were significantly greater in the rats on a low salt diet, while corticosterone was similar in both groups (71). This suggests that MR transcription in the PVN may be modulated by aldosterone as reported from in vitro studies (315, 461).…”

Mineralocorticoid regulation of cell function: the role of rapid signalling and gene transcription pathways

“…An exception occurs where the related enzyme HSD11B1 is expressed, without co-expression of hexose-6-phosphate dehydrogenase (H6PD). H6PD generates the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), without which HSD11B1 shifts its role from reductase to dehydrogenase, metabolising cortisol to cortisone (Hewitt et al 2005, Chen et al 2014. Transgenic mice overexpressing HSD11B2 in cardiomyocytes develop dilated cardiomyopathy and fibrosis, which is attenuated with MR antagonism (Qin et al 2003), implying that basal cardiac MR occupancy by endogenous glucocorticoid is protective against activation.…”