AIMS:Molecular clocks in the vasculature contribute to the normal circadian blood pressure (BP) rhythm. Glucocorticoids are known to synchronize molecular clocks within peripheral tissues. Disruption of the endogenous glucocorticoid rhythm causes 'non-dipping', a BP pattern associated with elevated cardiovascular risk. The mechanisms for this are unclear but vascular changes likely contribute. We examined the effect of impaired glucocorticoid rhythmicity on the time-of-day dependent vascular function and define the circadian transcriptome under control conditions and under arrhythmic glucocorticoids. METHODS AND RESULTS:Male C57BL6J mice kept on a 12:12 h light/dark cycle were implanted with a subcutaneous slow-release pellet containing vehicle or corticosterone (∼3.7 mg/kg/day), which flattened the endogenous glucocorticoid rhythm. After 7 days, renal arteries were isolated at 7am and 7pm to measure vasoreactivity using wire myography. Other arteries were taken 2-hourly over a 48 h period for RNA sequencing. In control arteries, endothelium-dependent and independent vasodilation was elevated at wake-phase compared to the sleep-phase. This temporal variation was absent in the renal arteries from corticosterone treated mice. Using CircaCompare and LimoRhyde, we found circadian rhythms in 459 of the 14 225 protein-coding transcripts in control arteries. Following corticosterone treatment, circadian rhythmicity was no longer detected in 156 genes, including genes involved in 'peroxide homeostasis' such as Nox4, and 'TNF signaling' like Mmp14. Paradoxically 492 genes gained rhythmicity with most related to mitochondrial activity. CONCLUSION:This study expands the molecular landscape for understanding circadian vascular physiology and emphasizes the impact of glucocorticoid rhythm on temporal changes in gene expression and vascular function. This is clinically relevant to the pathogenesis of vascular dysfunction associated with perturbed glucocorticoid signaling, for example in metabolic syndrome and chronic stress.

BACKGROUND:Cushing syndrome causes hypertension and increased cardiovascular risk. The hypertensive mechanisms are not clearly defined. We hypothesized that glucocorticoid excess would induce salt-sensitivity, reflecting an impaired pressure-natriuresis response and abnormal salt handling by the kidney. METHODS:We modeled Cushing syndrome in male C57BL/6J mice with prolonged adrenocorticotropic hormone (ACTH) infusion and measured blood pressure on a control diet and following high-salt intake. In a separate group, we assessed renal function and salt excretion, the in vivo pressure-natriuresis response, and ex vivo artery function. RESULTS:ACTH infusion increased blood pressure, induced nondipping and caused a transition to salt-sensitivity. ACTH infusion reduced the urine sodium/potassium ratio and abolished the diurnal rhythm of sodium excretion. In isolated renal artery, the response to nitric oxide was diminished, and at the mRNA level, we found evidence of arterial remodeling and enhanced TGF-β (transforming growth factor beta) signaling. Autoregulation of renal blood flow was impaired, as was the pressure-natriuresis response. CONCLUSIONS:ACTH infusion impairs sodium excretion and causes a transition to nondipping and salt-sensitive blood pressure. Renal hemodynamic and tubular abnormalities impair the pressure-natriuresis response. Our findings provide a landscape of the complex physiological response to ACTH excess that may contribute to poor cardiovascular health in Cushing syndrome.

Approximately one in every 800 children is born with the severe aneuploid condition of Down syndrome (DS), a trisomy of chromosome 21. Low blood pressure (hypotension) is a common condition associated with DS and can have a significant impact on exercise tolerance and quality of life. Little is known about the factors driving this hypotensive phenotype, therefore therapeutic interventions are limited. Carbonyl reductase 1 (CBR1) is an enzyme contributing to the metabolism of prostaglandins, glucocorticoids, reactive oxygen species and neurotransmitters, encoded by a gene (CBR1) positioned on chromosome 21 with the potential to affect blood pressure. Utilising telemetric blood pressure measurement of genetically modified mice, we tested the hypothesis that CBR1 influences blood pressure and that its overexpression contributes to hypotension in DS by evaluating possible contributing mechanisms in vitro. In a mouse model of DS (Ts65Dn), which exhibits hypotension, CBR1 activity was increased and pharmacological inhibition of CBR1 ed to increased blood pressure. Mice heterozygous null for Cbr1 had reduced CBR1 enzyme activity and elevated blood pressure. Further experiments indicate that the underlying mechanisms include alterations in both sympathetic tone and prostaglandin metabolism. We conclude that CBR1 activity contributes to blood pressure homeostasis and inhibition of CBR1 may present a novel therapeutic opportunity to correct symptomatic hypotension in DS.

Cushing Syndrome arises from endogenous overproduction of ACTH by a tumour or is acquired through chronic exposure to glucocorticoid medication. Hypertension is a major complication, increasing cardiovascular risk, but underlying mechanisms are not clearly defined. To investigate kidney contributions to abnormal blood pressure, we infused male C57BL/6J mice with ACTH or vehicle for 14-21 days, inducing cardinal features of Cushing Syndrome. The renal pressure natriuresis response was measured under anaesthesia. Applied increases in blood pressure caused natriuresis and diuresis in all mice but this was significantly diminished in the ACTH group. Renal hemodynamics did not change with pressure in controls but increased in ACTH-treated mice which had an impaired autoregulatory index. The ex vivo contractile response of the renal artery to phenylephrine was diminished in Cushing Syndrome mice, as was endothelium-dependent and endothelium-independent relaxation. On 0.3% sodium diet, there was no evidence of sodium retention vin ACTH mice. The diurnal rhythm of sodium handling was perturbed, with more excretion in the sleep period and ACTH treatment induced a non-dipping BP profile. The Cushing Syndrome model also displayed enhanced salt preference and amplified salt-sensitive blood pressure. We report that Cushing Syndrome induces a cluster of phenotypes that imperil sodium homeostasis and impair blood pressure regulation. Hypertension, salt-sensitivity and non-dipping blood pressure are important cardiovascular risk factors and beyond Cushing Syndrome, our findings are relevant to obesity and the metabolic syndrome, in which tissue glucocorticoid homeostasis is abnormal. ### Competing Interest Statement The authors have declared no competing interest.

ABSTRACT High salt intake is common and contributes to poor cardiovascular health. Sustained cortisol excess also induces an adverse cardiovascular profile. Urinary cortisol excretion positively correlates with urinary sodium excretion. We hypothesised that this was due to hypothalamic-pituitary-adrenal axis activation by high salt intake. In male C57BL6/J mice, 2 weeks of high salt intake increased Crh and Pomc mRNA abundance in the hypothalamus and anterior pituitary, respectively and caused a sustained rise in plasma corticosterone. Plasma copeptin and anterior pituitary V1b receptor mRNA expression was elevated, which may contribute to basal HPA axis activation. Additionally, high salt intake amplified glucocorticoid response to restraint stress, indicative of enhanced HPA axis sensitivity. In the periphery, high salt intake reduced the binding capacity of corticosteroid-binding globulin, enhancing glucocorticoid bioavailability. Within several tissues, the expression of glucocorticoid-regenerating enzyme, 11β-hydroxysteroid dehydrogenase type 1, was increased and the glucocorticoid receptor downregulated. Overall, high salt intake increased glucocorticoid exposure in the hippocampus, anterior pituitary and liver. Chronic high salt intake amplifies basal and stress-induced glucocorticoid levels and resets glucocorticoid biology centrally, peripherally and within cells. This shows direct connectivity between salt homeostasis and HPA axis function. The cumulative effect is likely maladaptive and may contribute to the long-term health consequences of a high salt diet.

Healthy individuals exhibit blood pressure variation over a 24-hour period with higher blood pressure during wakefulness and lower blood pressure during sleep. Loss or disruption of the blood pressure circadian rhythm has been linked to adverse health outcomes, for example, cardiovascular disease, dementia, and chronic kidney disease. However, the current diagnostic and therapeutic approaches lack sufficient attention to the circadian rhythmicity of blood pressure. Sleep patterns, hormone release, eating habits, digestion, body temperature, renal and cardiovascular function, and other important host functions as well as gut microbiota exhibit circadian rhythms, and influence circadian rhythms of blood pressure. Potential benefits of nonpharmacologic interventions such as meal timing, and pharmacologic chronotherapeutic interventions, such as the bedtime administration of antihypertensive medications, have recently been suggested in some studies. However, the mechanisms underlying circadian rhythm-mediated blood pressure regulation and the efficacy of chronotherapy in hypertension remain unclear. This review summarizes the results of the National Heart, Lung, and Blood Institute workshop convened on October 27 to 29, 2021 to assess knowledge gaps and research opportunities in the study of circadian rhythm of blood pressure and chronotherapy for hypertension.

Dietary potassium (K+) supplementation is associated with a lowering effect in blood pressure (BP), but not all studies agree. Here, we examined the effects of short- and long-term K+ supplementation on BP in mice, whether differences depend on the accompanying anion or the sodium (Na+) intake and molecular alterations in the kidney that may underlie BP changes. Relative to the control diet, BP was higher in mice fed a high NaCl (1.57% Na+) diet for 7 weeks or fed a K+-free diet for 2 weeks. BP was highest on a K+-free/high NaCl diet. Commensurate with increased abundance and phosphorylation of the thiazide sensitive sodium-chloride-cotransporter (NCC) on the K+-free/high NaCl diet, BP returned to normal with thiazides. Three weeks of a high K+ diet (5% K+) increased BP (predominantly during the night) independently of dietary Na+ or anion intake. Conversely, 4 days of KCl feeding reduced BP. Both feeding periods resulted in lower NCC levels but in increased levels of cleaved (active) α and γ subunits of the epithelial Na+ channel ENaC. The elevated BP after chronic K+ feeding was reduced by amiloride but not thiazide. Our results suggest that dietary K+ has an optimal threshold where it may be most effective for cardiovascular health.

Molecular clocks control a daily transcriptional schedule that maintains tissue homeostasis. Glucocorticoids synchronize peripheral clocks with the master clock in the suprachiasmatic nucleus in response to ambient light. In humans and mice, arrhythmic glucocorticoids induce non-dipping blood pressure and vascular dysfunction. The mechanisms of this are poorly understood. We hypothesize that arrhythmic activation of the glucocorticoid receptor desynchronizes the molecular clock mechanism in the renal artery, a major component of blood pressure control, dysregulating normal function. Our aim was to dissect renal artery circadian physiology transcriptionally and functionally and interrogate the effect of arrhythmic glucocorticoids. Male mice, kept on a 12:12 light:dark cycle, were anesthetised with 4% isolflurane and implanted with a hypodermal pellet containing either vehicle or corticosterone (≈3.7 mg/kg per day), to flatten the endogenous glucocorticoid rhythm. After 7 days, mice were culled by cervical dislocation at 2hr intervals for 48 hours and the renal arteries taken. The renal artery circadian transcriptome was profiled using Illumina Truseq Stranded RNA-sequencing. Cosinor regression (Limorhyde) was applied to the control group and identified 465 of 14425 (~3%) protein coding transcripts with rhythmic expression (p<0.005 for fit to a cosinor waveform). Of these, 265 (62%) lost their rhythm in the corticosterone-treated group. These arrhythmic transcripts were interrogated by gene set enrichment analysis (Biological Process, FDR<0.05) and enriched gene sets were related to “Circadian Rhythm,” “Transforming growth factor beta” and “Smooth muscle proliferation.” Paradoxically, 919 transcripts gained de novo rhythmicity in the corticosterone group and were related to mitochondrial respiration and ATP synthesis. In parallel, we used wire myography to determine the diurnal variation in endothelium-independent vasodilation via sodium nitroprusside dose response. Renal arteries were taken from corticosterone and vehicle treated mice as described above, either during the active phase (subjective night) or inactive phase (subjective day). Data are mean ± SD and analysed by 2-way ANOVA. Vasodilation was higher during the night compared to the day in the control group, (night logEC50 =8.5±0.4 versus day logEC50 =7.5±0.4 p=0.01, n=12). In the corticosterone treated group circadian variability in vasodilation was blunted (night logEC50 =7.7±0.9 versus day logEC50=7.7±0.4, p=0.9, n=12). We speculate that temporal misalignment of the vascular molecular circadian machinery and the subsequent temporal changes in gene expression may have a direct effect on dilatory capacity. This novel study extends our understanding of circadian vascular physiology, undelining the impact of glucocorticoids on temporal gene expression.This may be clinically relevant in the pathogenesis of vascular dysfunction linked to elevated glucocorticoids in metabolic syndrome. This study was funded by the British Heart Foundation (PhD studentship code: FS/18/57/34178) and the Kidney Research UK (Intermediate Grant Code: INT_001_20181115 and IN_002_2021 0729). Analyses were carried out by Edinburgh Genomics at the University of Edinburgh. Edinburgh Genomics is partly supported through core grants from NERC (R8/H10/56), MRC (MR/K001744/1) and BBSRC (BB/J004243/1). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Nuclear receptors play a central role in both energy metabolism and cardiomyocyte death and survival in the heart. Recent evidence suggests they may also influence cardiomyocyte endowment. Although several members of the nuclear receptor family play key roles in heart maturation (including thyroid hormone receptors) and cardiac metabolism, here, the focus will be on the corticosteroid receptors, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). The heart is an important target for the actions of corticosteroids, yet the homeostatic role of GR and MR in the healthy heart has been elusive. However, MR antagonists are important in the treatment of heart failure, a condition associated with mitochondrial dysfunction and energy failure in cardiomyocytes leading to mitochondria-initiated cardiomyocyte death (Ingwall and Weiss, Circ Res 95:135-145, 2014; Ingwall , Cardiovasc Res 81:412-419, 2009; Zhou and Tian , J Clin Invest 128:3716-3726, 2018). In contrast, animal studies suggest GR activation in cardiomyocytes has a cardioprotective role, including in heart failure.

Acute kidney injury (AKI) is common and associated with increased risks of cardiovascular and chronic kidney disease. Causative molecular/physiological pathways are poorly defined. There are no therapies to improve long-term outcomes. An activated endothelin system promotes cardiovascular and kidney disease progression. We hypothesized a causal role for this in the transition of AKI to chronic disease. Plasma endothelin-1 was threefold higher; urine endothelin-1 was twofold higher; and kidney preproendothelin-1, endothelin-A, and endothelin-B receptor message up-regulated in patients with AKI. To show causality, AKI was induced in mice by prolonged ischemia with a 4-week follow-up. Ischemic injury resulted in hypertension, endothelium-dependent and endothelium-independent macrovascular and microvascular dysfunction, and an increase in circulating inflammatory Ly6C high monocytes. In the kidney, we observed fibrosis, microvascular rarefaction, and inflammation. Administration of endothelin-A antagonist, but not dual endothelin-A/B antagonist, normalized blood pressure, improved macrovascular and microvascular function, and prevented the transition of AKI to CKD. Endothelin-A blockade reduced circulating and renal proinflammatory Ly6C high monocytes and B cells, and promoted recruitment of anti-inflammatory Ly6C low monocytes to the kidney. Blood pressure reduction alone provided no benefits; blood pressure reduction alongside blockade of the endothelin system was as effective as endothelin-A antagonism in mitigating the long-term sequelae of AKI in mice. Our studies suggest up-regulation of the endothelin system in patients with AKI and show in mice that existing drugs that block the endothelin system, particularly those coupling vascular support and anti-inflammatory action, can prevent the transition of AKI to chronic kidney and cardiovascular disease.

In the latest edition of Acta Physiologica, Khbouz et al1 identify the dual specificity phosphatase 3 (DUSP3) as a potential target for preventing injury following ischaemia/ reperfusion in the kidney. Renal ischaemia/reperfusion injury (IRI) is caused by both the initial insult, a temporary interruption or reduction of blood flow to the kidney, and a subsequent insult that occurs upon the restoration of renal blood flow. IRI results in both tubular and haemodynamic dysfunction. Tubular injury is particularly prominent in the proximal tubule because of its dependence on oxygen. Haemodynamic dysfunction results from both endothelial dysfunction in arteries and arterioles and microvascular loss. IRI is the leading cause of acute kidney injury (AKI). AKI is common with an incidence of 10%15% of all hospital admissions across the globe.2 There is high mortality associated with AKI and those that survive have an increased risk of progression to chronic kidney disease.2 IRI occurs in clinical contexts such as hypovolaemic shock, renal stenosis and cardiothoracic surgery. IRI is an unavoidable consequence of kidney transplant surgery and can lead to delayed graft function and acute graft rejection.3 With approximately 100 000 renal transplantations performed globally in 2019 alone,4 strategies to prevent IRIinduced tissue damage and its sequelae are needed. It is possible to reduce the injury caused by an ischaemic/ reperfusion event. There is a body of evidence demonstrating that organs, including the kidney, can be primed to better tolerate an ischaemic insult by employing an ischaemic preconditioning strategy.5,6 Ischaemic preconditioning evokes a systemic response and strategies to induce it involve exposing the target organ or even a remote organ to short, nonlethal bouts of ischaemia/reperfusion. This manoeuvre provides protection following a subsequent ischaemic episode. The mechanisms underlying the protection afforded by ischaemic conditioning remain undefined but likely include an improvement in vascularization and modulation of the innate immune system. Khbouz et al1 propose the involvement of DUSP3 in renal ischaemic conditioning. DUSP3 (comprehensively reviewed in ref [7]) is a dualspecific atypical protein tyrosine phosphatase that dephosphorylates tyrosine and threonine residues including those in ERK1/2. A lack of an MAPKbinding domain makes it atypical compared to the other dual specificity phosphatases. DUSP3 has diverse biological functions, spanning roles in cell cycle arrest and senescence to angiogenesis and immune response mediation. Prior to Khbouz et al’s exciting work, a global DUSP3−/− mouse was generated and found resistant to LPSinduced endotoxic shock and polymicrobial infectioninduced shock.8 DUSP3−/− had a modulated innate immune cell response: DUSP3−/− mice had more M2like reparative macrophages at baseline and retained these considerable better than controls following septic shock induction.8 Crucially, transfer of monocytes from DUSP3−/− donor mice conferred full resistance to LPSinduced sepsis in recipient DUSP+/+ mice.8 IRI is a form of sterile inflammation, thus Khbouz et al1 hypothesized that the benefits of DUSP3 knockout on minimizing an aberrant inflammatory response in sepsis may also apply to IRI. First, in healthy control mice, Khbouz et al demonstrate that DUSP3 colocalizes with markers of podocytes and endothelial cells in the kidney. The levels of renal DUSP3 mRNA and protein increased in control mice following IRI and immunohistochemistry analysis revealed that postIRI, DUSP3 colocalized with markers of proximal tubule cells in addition to podocytes and endothelial cells. DUSP3−/− mice were remarkably resistant to IRI compared to controls. GFR was maintained and albuminuria was reduced by half of the control IRI mice. DUSP3−/− mice resisted renal injury with levels of urinary alpha1microglobulin (signalling proximal tubule dysfunction) comparable to preIRI levels, serum levels of blood urea nitrogen (BUN) and Jablonski scores postIRI reduced compared to controls and renal Kim1 mRNA levels 18fold lower than control IRI kidneys. There are hints that as in septic shock, loss of DUSP3 in IRI caused attenuation of the innate immune system, with inflammatory markers (IL1ß, CD11b, IL6 and TNFα) and F480 positive macrophages reduced.1

Glucocorticoids synchronise peripheral clocks with the master clock in the suprachiasmatic nucleus in response to the ambient light cycle. In humans and mice, arrhythmic glucocorticoids induce non-dipping blood pressure and vascular dysfunction. The mechanisms of this are poorly understood. We hypothesize that arrhythmic activation of the glucocorticoid receptor attenuates the circadian clock signalling in the vasculature leading to changes in blood pressure. To test this hypothesis, we assessed vascular function and blood pressure rhythms in control mice and mice with smooth muscle specific deletion of the glucocorticoid receptor (SMGRKO). Renal and mesenteric arteries were isolated at 7am (ZT0; lights on) and 7pm (ZT12; lights off), mounted on a wire myograph and the responses to increasing doses of phenylephrine or sodium nitroprusside (SNP) assessed. In wild-type mice, the sensitivity of the renal artery to phenylephrine-mediated contraction was greater at ZT12 than at ZT0, by comparing the half maximal effective concentration of each group, (logEC 7.54±0.26 versus 7.29±0.17 respectively; p=0.04). The sensitivity to SNP-mediated relaxation was also greater when measured at ZT12 compared to ZT0 (7.64±0.3 versus 7.09±0.5; p=0.03). Similar responses were also detected in the mesenteric arteries. In SMGRKO mice, the temporal differences in renal and mesenteric artery vascular reactivity were absent. We used radiotelemetry to assess the effect of this altered rhythm of vascular reactivity on blood pressure. SMGRKO had significantly lower systolic blood pressure throughout the 24h cycle compared to wild-type littermates, both when lights were off (107.9 ± 22.13 versus 136.3 ± 17.17 mmHg respectively; p=0.015) and during the lights on period (99.6 ± 13.16 versus 118 ± 15.9 mmHg; p=0.014). Blood pressure rhythmicity was not altered in SMGRKO mice. These data show that the glucocorticoid receptor signalling in vascular smooth muscle contributes both to the diurnal variation of vascular reactivity and to blood pressure, but loss of the receptor does not affect blood pressure rhythm. Whether glucocorticoid receptor deletion in smooth muscle protects against non-dipping blood pressure induced by glucocorticoids needs further investigation.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Objective: Abnormal blood pressure (BP) rhythms precede and predict cardiovascular disease and are often linked with salt-sensitivity. The mechanisms underlying these rhythms are unknown. High dietary salt intake can cause phase shifts in the intrinsic circadian clocks within peripheral organs but the implications for BP rhythm are unclear. We investigated the effect of a high salt diet on the rhythms of BP, heart rate (HR) and activity. Design and method: BP was monitored by radiotelemetry in male C57BL6/J mice. After 1 week of 0.25% Na+ chow (baseline), mice received 3% Na+ diet for 3 weeks followed by 0.25% Na+ for a further 2 weeks (Na+ washout). Systolic BP (SBP), HR and activity data was analysed by cosinor analysis. Sympathetic nervous system activity was estimated by measuring 12 h urinary catecholamine spillover and plasma aldosterone was measured following a week of 3% Na+ diet. Results: Mesor (circadian mean) SBP increased by 7mmHg after week 1 of 3% Na+ diet. This was maintained over 3 weeks but reduced to baseline after Na+ washout. BP amplitude increased from 9mmHg (baseline) to 14mmHg within 1 week of 3% Na+ feeding. This was maintained for the 3 weeks of 3% Na+ but reduced to 8mmHg following Na+ washout. This reflected elevated active-phase BP rather than enhanced dip in sleep-phase BP. A ∼4.5-hour phase delay in SBP was observed in the second week of 3% Na+ diet. HR mesor did not change throughout the experiment but amplitude was elevated at 3 weeks of 3% Na+. Activity amplitude increased during the first week of 3% Na+ intake but was not maintained at week 2. Plasma aldosterone was appropriately suppressed but day and night urinary adrenaline levels were increased after 1 week on 3% Na+ diet. Conclusions: C57BL6/J mice exhibit salt-sensitive BP. A 3% Na+ diet altered BP rhythm by increasing amplitude and inducing a modest phase shift. Further studies are needed to investigate the role of the sympathetic system and intrinsic molecular clocks in the induction of these rhythms. This may give insights into mechanisms underlying the relationship between salt-sensitivity and abnormal BP rhythms.

We discovered high Na+ and water content in the skin of newborn Sprague–Dawley rats, which reduced ~ 2.5-fold by 7 days of age, indicating rapid changes in extracellular volume (ECV). Equivalent changes in ECV post birth were also observed in C57Bl/6 J mice, with a fourfold reduction over 7 days, to approximately adult levels. This established the generality of increased ECV at birth. We investigated early sodium and water handling in neonates from a second rat strain, Fischer, and an Hsd11b2-knockout rat modelling the syndrome of apparent mineralocorticoid excess (SAME). Despite Hsd11b2−/− animals exhibiting lower skin Na+ and water levels than controls at birth, they retained ~ 30% higher Na+ content in their pelts at the expense of K+ thereafter. Hsd11b2−/− neonates exhibited incipient hypokalaemia from 15 days of age and became increasingly polydipsic and polyuric from weaning. As with adults, they excreted a high proportion of ingested Na+ through the kidney, (56.15 ± 8.21% versus control 34.15 ± 8.23%; n = 4; P < 0.0001), suggesting that changes in nephron electrolyte transporters identified in adults, by RNA-seq analysis, occur by 4 weeks of age. Our data reveal that Na+ imbalance in the Hsd11b2−/− neonate leads to excess Na+ storage in skin and incipient hypokalaemia, which, together with increased, glucocorticoid-induced Na+ uptake in the kidney, then contribute to progressive, volume contracted, salt-sensitive hypertension. Skin Na+ plays an important role in the development of SAME but, equally, may play a key physiological role at birth, supporting post-natal growth, as an innate barrier to infection or as a rudimentary kidney.

ABSTRACTThe late gestational rise in glucocorticoids contributes to the structural and functional maturation of the perinatal heart. Here, we hypothesised that glucocorticoid action contributes to the metabolic switch in perinatal cardiomyocytes from carbohydrate to fatty acid oxidation. In primary mouse fetal cardiomyocytes, dexamethasone treatment induced expression of genes involved in fatty acid oxidation and increased mitochondrial oxidation of palmitate, dependent upon glucocorticoid receptor (GR). Dexamethasone did not, however, induce mitophagy or alter the morphology of the mitochondrial network. In neonatal mice, dexamethasone treatment induced cardiac expression of fatty acid oxidation genes in vivo. However, dexamethasone treatment of pregnant C57Bl/6 mice at embryonic day (E)13.5 or E16.5 failed to induce fatty acid oxidation genes in fetal hearts assessed 24 hours later. Instead, at E17.5, fatty acid oxidation genes were down-regulated by dexamethasone, as was GR itself. PGC-1α, required for glucocorticoid-induced maturation of primary mouse fetal cardiomyocytes in vitro, was down-regulated in vivo in fetal hearts at E17.5, 24 hours after dexamethasone administration. Similarly, following a course of antenatal corticosteroids in a sheep model of preterm birth, both GR and PGC-1α were down-regulated in fetal heart. These data suggest endogenous glucocorticoids support the perinatal switch to fatty acid oxidation in cardiomyocytes through changes in gene expression rather than gross changes in mitochondrial volume or mitochondrial turnover. Moreover, our data suggest that treatment with exogenous glucocorticoids may interfere with normal fetal heart maturation, possibly by down-regulating GR. This has implications for clinical use of antenatal corticosteroids when preterm birth is considered a possibility.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)