Renal and Blood Pressure Response to a High-Salt Diet in Mice With Reduced Global Expression of the Glucocorticoid Receptor

Ivy,; Evans, Louise; Moorhouse, Rebecca; Richardson, Rachel; Al-Dujaili, Emad A S; Flatman, Peter W.; Kenyon, Christopher J.; Chapman, Karen; Bailey, Matthew A.

doi:10.3389/fphys.2018.00848

Cited by 14 publications

(14 citation statements)

References 54 publications

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“…We confirmed the diurnal rhythm of pNCC (19,49), further finding that chronic systemic GR antagonism perturbed this rhythm. This prompted assessment of diurnal variation in pNCC in mice with a genetically induced reduction in GR expression (18,27). We were only able to assess pNCC in GR heterozygote null mice at two time points using archived kidney protein homogenates, the midpoints of the subjective day and night, but our data indicate that reduced GR expression significantly dampened the pNCC phosphorylation rhythm.…”

Section: Discussionmentioning

confidence: 90%

Glucocorticoid receptor activation stimulates the sodium-chloride cotransporter and influences the diurnal rhythm of its phosphorylation

Ivy

Jones

Costello

et al. 2019

American Journal of Physiology-Renal Physiology

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The sodium-chloride cotransporter (NCC) in the distal convoluted tubule contributes importantly to sodium balance and blood pressure (BP) regulation. NCC phosphorylation determines transport activity and has a diurnal rhythm influenced by glucocorticoids. Disturbing this rhythm induces “nondipping” BP, an abnormality that increases cardiovascular risk. The receptor through which glucocorticoids regulate NCC is not known. In this study, we found that acute administration of corticosterone to male C57BL6 mice doubled NCC phosphorylation without affecting total NCC abundance in both adrenalectomized and adrenal-intact mice. Corticosterone also increased the whole kidney expression of canonical clock genes: period circadian protein homolog 1 ( Per1), Per2, cryptochrome 1, and aryl hydrocarbon receptor nuclear translocator-like protein 1. In adrenal-intact mice, chronic blockade of glucocorticoid receptor (GR) with RU486 did not change total NCC but prevented corticosterone-induced NCC phosphorylation and activation of clock genes. Blockade of mineralocorticoid receptor (MR) with spironolactone reduced the total pool of NCC but did not affect stimulation by corticosterone. The diurnal rhythm of NCC phosphorylation, measured at 6-h intervals, was blunted by chronic GR blockade, and a similar dampening of diurnal variation was seen in GR heterozygous null mice. These effects on NCC phosphorylation did not reflect altered rhythmicity of plasma corticosterone or serum and glucocorticoid-induced kinase 1 activity. Both mineralocorticoids and glucocorticoids emerge as regulators of NCC, acting via distinct receptor pathways. MR activation provides maintenance of the NCC protein pool; GR activation dynamically regulates NCC phosphorylation and establishes the diurnal rhythm of NCC activity. This study has implications for circadian BP homeostasis, particularly in individuals with abnormal glucocorticoid signaling as is found in chronic stress and corticosteroid therapy.

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Section: Discussionmentioning

confidence: 90%

Glucocorticoid receptor activation stimulates the sodium-chloride cotransporter and influences the diurnal rhythm of its phosphorylation

Ivy

Jones

Costello

et al. 2019

American Journal of Physiology-Renal Physiology

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“…Previous in vitro and in vivo studies proposed a role of GR in renal MR-mediated Na + transport in a compensatory and/or cooperative manner (Berger et al, 1998; Gaeggeler et al, 2005; Hunter et al, 2014; Canonica et al, 2016; Terker et al, 2016; Ivy et al, 2018), although it could not yet be functionally confirmed. In this study, we used adult inducible nephron-specific GR knockout ( Nr3c1 Pax8/LC1 ) mice to explore the consequences of renal tubular GR deletion for Na + handling and blood pressure regulation.…”

Section: Discussionmentioning

confidence: 94%

“…Ivy and coworkers recently reported that mice with global GR haploinsufficiency exhibit increased blood pressure that is further increased by high salt diet. In this model, corticosterone, and to a lesser extent deoxycorticosterone excretion, was increased in mutant mice following a high-salt challenge, that may lead to systemic effects (Ivy et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Lack of Renal Tubular Glucocorticoid Receptor Decreases the Thiazide-Sensitive Na+/Cl– Cotransporter NCC and Transiently Affects Sodium Handling

Canonica¹,

Frateschi²,

Boscardin³

et al. 2019

Front. Physiol.

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Chronic glucocorticoid infusion impairs NCC activity and induces a non-dipping profile in mice, suggesting that glucocorticoids are essential for daily blood pressure variations. In this paper, we studied mice lacking the renal tubular glucocorticoid receptor (GR) in adulthood (GR knockouts, Nr3c1 Pax8/LC1 ). Upon standard salt diet, Nr3c1 Pax8/LC1 mice grow normally, but show reduced NCC activity despite normal plasma aldosterone levels. Following diet switch to low sodium, Nr3c1 Pax8/LC1 mice exhibit a transient but significant reduction in the activity of NCC and expression of NHE3 and NKCC2 accompanied by significant increased Spak activity. This is followed by transiently increased urinary sodium excretion and higher plasma aldosterone concentrations. Plasma corticosterone levels and 11βHSD2 mRNA expression and activity in the whole kidney remain unchanged. High salt diet does not affect whole body Na + and/or K + balance and NCC activity is not reduced, but leads to a significant increase in diastolic blood pressure dipping in Nr3c1 Pax8/LC1 mice. When high sodium treatment is followed by 48 h of darkness, NCC abundance is reduced in knockout mice although activity is not different. Our data show that upon Na + restriction renal tubular GR-deficiency transiently affects Na + handling and transport pathways. Overall, upon standard, low Na + and high Na + diet exposure Na + and K + balance is maintained as evidenced by normal plasma and urinary Na + and K + and aldosterone concentrations.

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“…However, it is not enough to counteract GR actions to increase blood pressure. Perhaps, this response also includes the action of mineralocorticoids as seen in mice with GR haploinsufficiency (Ivy et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone Causes Hypertension in Rats Even Under Chemical Blockade of Peripheral Sympathetic Nerves

et al. 2019

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Synthetic glucocorticoids (GCs) are widely used to treat inflammatory conditions. However, chronic use of GCs can lead to hypertension. The cause of this undesired side effect remains unclear. Previously, we developed an in vivo rat model to study the mechanisms underlying hypertension induced by the chronic administration of the potent synthetic GC, dexamethasone (DEX) and found that the catecholamine biosynthetic pathway plays an important role. In the current study, we used this model to investigate the role of the adrenal medulla, renal nerves, and other peripheral sympathetic nerves in DEX-induced hypertension. After 5 days of baseline telemetric recording of mean arterial pressure (MAP) and heart rate (HR), rats were subjected to one of the following treatments: renal denervation (RDNX), adrenal medullectomy (ADMX), 6-hydroxydopamine (6-OHDA, 20 mg/kg, i.p.) to induce chemical sympathectomy, or a combination of ADMX and 6-OHDA. On day 11, the animals received vehicle (VEH) or DEX in drinking water for 7 days, with the latter causing an increase in MAP in control animals. ADMX and RDNX by themselves exacerbated the pressor effect of DEX. In the chemical sympathectomy group, DEX still caused a rise in MAP but the response was lower (ΔMAP of 6-OHDA/DEX < VEH/DEX, p = 0.039). However, when ΔMAP was normalized to day 10, 6-OHDA + DEX did not show any difference from VEH + DEX, certainly not an increase as observed in DEX + ADMX or RDNX groups. This indicates that sympathetic nerves do not modulate the pressor effect of DEX. TH mRNA levels increased in the adrenal medulla in both VEH/DEX (p = 0.009) and 6-OHDA/DEX (p = 0.031) groups. In the 6-OHDA group, DEX also increased plasma levels of norepinephrine (NE) (p = 0.016). Our results suggest that the activation of catecholamine synthetic pathway could be involved in the pressor response to DEX in animals even under chemical sympathectomy with 6-OHDA.

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Renal and Blood Pressure Response to a High-Salt Diet in Mice With Reduced Global Expression of the Glucocorticoid Receptor

Cited by 14 publications

References 54 publications

Glucocorticoid receptor activation stimulates the sodium-chloride cotransporter and influences the diurnal rhythm of its phosphorylation

Glucocorticoid receptor activation stimulates the sodium-chloride cotransporter and influences the diurnal rhythm of its phosphorylation

Lack of Renal Tubular Glucocorticoid Receptor Decreases the Thiazide-Sensitive Na+/Cl– Cotransporter NCC and Transiently Affects Sodium Handling

Dexamethasone Causes Hypertension in Rats Even Under Chemical Blockade of Peripheral Sympathetic Nerves

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