Biology subjects

Ivy, J. R.

Publications and source records attributed to Ivy, J. R..

5 recordsLinked to original sources

bioRxiv2025

Loss of circulating glucocorticoid rhythm disrupts the circadian transcriptome and vascular reactivity in the mouse renal artery

AimsMolecular clocks in the vasculature contribute to the normal circadian blood pressure (BP) rhythm. Glucocorticoids are known to synchronise 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 ResultsMale C57BL6J mice kept on a 12:12 hour light/dark cycle were implanted with a subcutaneous slow-release pellet containing vehicle or corticosterone ([~]3.7mg/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-hour 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, 156 genes lost their rhythm, including canonical clock genes, genes involved in "peroxide homeostasis" such as Nox4 and "TNF signalling" like Mmp14. Paradoxically 492 genes gained a rhythm and were predominantly mitochondrial-related. ConclusionsThis study expands the molecular landscape for understanding circadian vascular physiology and emphasises 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 signalling for e.g. in metabolic syndrome and chronic stress. TRANSLATIONAL PERSPECTIVEDisruption of the normal circadian rhythm of plasma glucocorticoid levels causes non-dipping blood pressure, a profile associated with enhanced cardiovascular risk. The role of vascular dysfunction in this context is unknown. We report that arrhythmic plasma glucocorticoid levels impair time-dependent vasoreactivity and alters the circadian transcriptome of the renal artery. We provide a molecular framework for investigations into glucocorticoid-induced vascular dysfunction across the 24-hour day. Clinically, this is relevant for patients on chronic glucocorticoid therapy but could have generalisable implications for the underlying mechanisms of blood pressure rhythm. Targeting rhythm-sensitive vascular pathways may offer novel avenues to improve blood pressure rhythms. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/650449v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1c988b8org.highwire.dtl.DTLVardef@2f0ee7org.highwire.dtl.DTLVardef@17b6e25org.highwire.dtl.DTLVardef@7c6afb_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2024

Renal arterial dysfunction, impaired pressure natriuresis and salt-sensitivity in a mouse model of Cushing syndrome

BackgroundCushing 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. MethodsWe 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 anesthesia and ex vivo artery function assessed by myography. ResultsACTH infusion blunted the natriuretic and diuretic responses to incremental increases in blood pressure. Renal hemodynamics did not change with blood pressure in controls, but renal autoregulation was impaired in ACTH mice. 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 in ACTH-treated mice but the diurnal rhythm of sodium excretion was abnormal and mice had non-dipping BP. The Cushing Syndrome model also displayed enhanced salt preference and amplified salt-sensitive blood pressure. ConclusionCushing Syndrome induces a cluster of phenotypes impacting sodium homeostasis and 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.

physiology↗

bioRxiv2022

High salt intake activates the hypothalamic-pituitary-adrenal axis, amplifies the stress response, and alters tissue glucocorticoid exposure in mice

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, 11{beta}-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.

physiology↗

bioRxiv2021

GLUCOCORTICOIDS REGULATE MITOCHONDRIAL FATTY ACID OXIDATION IN FETAL CARDIOMYOCYTES

The 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-1, 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-1 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.

physiology↗

bioRxiv2019

A detailed graphical and computational model of the mammalian renal circadian clock

Here we describe the construction of a detailed graphical and computational model of the mammalian circadian clock. We use it to simulate the clock activity within the kidney, where it plays a pivotal role in regulating blood pressure. First, we assembled a network-based process diagram, which includes all known components of the clock and the interactions between them. Parameterisation of the model for Petri net-based simulation experiments used mRNA levels in the kidney to define initial conditions. With empirical testing, model parameterisation was further refined such that the simulated activity of core genes closely matched their measured activity. Furthermore, virtual knockout experiments performed on the model were shown to reflect experimental gene knockout data. It also identified points at which canonical clock genes may integrate with downstream genes likely to affect blood pressure and other aspects of kidney function. We believe that the model provides new insights into the complexity and function of this most central of physiological pathways and provides a valuable resource for the research community.

systems biology↗