Biology subjects

Ashton, N.

Publications and source records attributed to Ashton, N..

3 recordsLinked to original sources

bioRxiv2021

Impact of maternal intermittent fasting during pregnancy on cardiovascular, metabolic and renal function in adult rat offspring

Pregnant Muslim women are exempt from fasting during Ramadan; however a majority are reported to fast. The impact of this form of maternal intermittent fasting (IF) on fetal development and offspring health is not well defined. Using a rat model, we have shown previously that maternal IF results in fetal growth restriction accompanied by changes in placental nutrient transport function. The aim of this study was to assess cardiovascular, metabolic and renal function in adult offspring of IF-exposed dams. Food was withheld from Wistar rats from 17:00 to 09:00 daily throughout pregnancy; controls had ad libitum access to food. Birth weight was unaffected; however male IF pups grew more slowly up to 10 weeks of age (P < 0.01) whereas IF females matched their control counterparts. Systolic blood pressure (SBP), glucose tolerance and basal renal function at 14 weeks were not affected by IF exposure. When offered saline solutions (0.9-2.1%) to drink, females showed a greater salt preference than males (P < 0.01); however there were no differences between dietary groups. A separate group of pups was weaned onto a 4% NaCl diet. SBP increased in IF pups sooner, at 7 weeks (P < 0.01), than controls which became hypertensive from 10 weeks. Renal function did not appear to differ; however markers of renal injury were elevated in IF males (P < 0.05). Maternal IF does not affect resting cardiovascular, metabolic and renal function; but when challenged by dietary salt load male IF offspring are more prone to renal injury.

physiology↗

bioRxiv2020

Loss of PKCα increases arterial medial calcification in a uremic mouse model of chronic kidney disease

Arterial medial calcification is an independent risk factor for mortality in chronic kidney disease. We previously reported that knock-down of PKC expression increases high phosphate-induced mineral deposition by vascular smooth muscle cells in vitro. This new study tests the hypothesis that PKC regulates uremia-induced medial calcification in vivo. Female wild-type and PKC-/- mice underwent a two-stage subtotal nephrectomy and were fed a high phosphate diet for 8 weeks. X-ray micro computed tomography demonstrated that uremia-induced medial calcification was increased in the abdominal aorta and aortic arch of PKC-/- mice compared to wild-types. Blood urea nitrogen was also increased in PKC-/- mice compared to wild-types; there was no correlation between blood urea nitrogen and calcification in PKC-/- mice. Phosphorylated SMAD2 immunostaining was detected in calcified aortic arches from uremic PKC-/- mice; the osteogenic marker Runx2 was also detected in these areas. No phosphorylated SMAD2 staining were detected in calcified arches from uremic wild-types. PKC knock-down increased TGF-{beta}1-induced SMAD2 phosphorylation in vascular smooth muscle cells in vitro, whereas the PKC activator prostratin decreased SMAD2 phosphorylation. In conclusion, loss of PKC increases uremia-induced medial calcification. The PKC/TGF-{beta} signaling axis could therefore represent a new therapeutic target for arterial medial calcification in chronic kidney disease.

cell biology↗

bioRxiv2019

Circadian control of intrinsic heart rate via a sinus node clock and the pacemaker channel

In the human, there is a circadian rhythm in the resting heart rate and it is higher during the day in preparation for physical activity. Conversely, slow heart rhythms (bradyarrhythmias) occur primarily at night. Although the lower heart rate at night is widely assumed to be neural in origin (the result of high vagal tone), the objective of the study was to test whether there is an intrinsic change in heart rate driven by a local circadian clock. In the mouse, there was a circadian rhythm in the heart rate in vivo in the conscious telemetrized animal, but there was also a circadian rhythm in the intrinsic heart rate in denervated preparations: the Langendorff-perfused heart and isolated sinus node. In the sinus node, experiments (qPCR and bioluminescence recordings in mice with a Per1 luciferase reporter) revealed functioning canonical clock genes, e.g. Bmal1 and Per1. We identified a circadian rhythm in the expression of key ion channels, notably the pacemaker channel Hcn4 (mRNA and protein) and the corresponding ionic current (funny current, measured by whole cell patch clamp in isolated sinus node cells). Block of funny current in the isolated sinus node abolished the circadian rhythm in the intrinsic heart rate. Incapacitating the local clock (by cardiac-specific knockout of Bmal1) abolished the normal circadian rhythm of Hcn4, funny current and the intrinsic heart rate. Chromatin immunoprecipitation demonstrated that Hcn4 is a transcriptional target of BMAL1 establishing a pathway by which the local clock can regulate heart rate. In conclusion, there is a circadian rhythm in the intrinsic heart rate as a result of a local circadian clock in the sinus node that drives rhythmic expression of Hcn4. The data reveal a novel regulator of heart rate and mechanistic insight into the occurrence of bradyarrhythmias at night.

physiology↗