Biology subjects

Grenier, C.

Publications and source records attributed to Grenier, C..

9 recordsLinked to original sources

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↗

bioRxiv2024

Integrin alpha1 beta1 promotes interstitial fibrosis in a mouse model of polycystic kidney disease

Fibrosis is the cause of end-stage kidney failure in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). The molecular and cellular mechanisms involved in fibrosis are complex and anti-fibrotic therapies have so far failed to make an impact on patient welfare. Using unbiased proteomics analysis on the Pkd1nl/nl mouse, we found that expression of the integrin 1 subunit is increased in this model of ADPKD. In human ADPKD tissue and two single cell RNA kidney disease datasets, ITGA1 was also upregulated. To investigate the functional role of this integrin subunit in ADPKD, we generated a Pkd1nl/nlItga1-/- mouse. We observed a significant reduction in kidney volume and kidney dysfunction in mice lacking the integrin 1 subunit. Kidneys from Pkd1nl/nlItga1-/- mice had smaller cysts and reduced interstitial expansion and tubular atrophy. Picrosirius red staining identified a restriction in collagen staining in the interstitium and the myofibroblast marker smooth muscle actin was also downregulated. Myofibroblast cell proliferation was reduced in Pkd1nl/nlItga1-/- mice and primary fibroblast cultures demonstrated an abrogated fibrogenic phenotype in integrin 1-depleted fibroblasts. These results highlight a previously unrecognised role for the integrin 1 subunit in kidney fibrosis.

pathology↗

bioRxiv2024

Performance of phenomic selection in rice: effects of population size and genotype-environment interactions on predictive ability

Phenomic prediction (PP), a novel approach utilizing Near Infrared Spectroscopy (NIRS) data, offers an alternative to genomic prediction (GP) for breeding applications. In PP, a hyperspectral relationship matrix replaces the genomic relationship matrix, potentially capturing both additive and non-additive genetic effects. While PP boasts advantages in cost and throughput compared to GP, the factors influencing its accuracy remain unclear and need to be defined. This study investigated the impact of various factors, namely the training population size, the multi-environment information integration, and the incorporations of genotype x environment (GxE) effects, on PP compared to GP. We evaluated the prediction accuracies for several agronomically important traits (days to flowering, plant height, yield, harvest index, thousand-grain weight, and grain nitrogen content) in a rice diversity panel grown in four distinct environments. Training population size and GxE effects inclusion had minimal influence on PP accuracy. The key factor impacting the accuracy of PP was the number of environments included. Using data from a single environment, GP generally outperformed PP. However, with data from multiple environments, using genotypic random effect and relationship matrix per environment, PP achieved comparable accuracies to GP. Combining PP and GP information did not significantly improve predictions compared to the best model using a single source of information (e.g., average predictive ability of GP, PP, and combined GP and PP for grain yield were of 0.44, 0.42, and 0.44, respectively). Our findings suggest that PP can be as accurate as GP when all genotypes have at least one NIRS measurement, potentially offering significant advantages for rice breeding programs. Authors SummaryThis study explores the interest of phenomic selection within the context of rice breeding. Unlike genomic selection, phenomic selection utilizes near-infrared spectroscopic (NIRS) technology to predict genotypes performance. The importance of this methodology lies in its capacity to reduce the costs and enhance the genetic gains of breeding programs, particularly in developing countries where genomic information is not always easily accessible (cost, availability, ease of use). Also, NIRS technology is often already available, even in resource-constrained breeding programs. By focusing the study on rice, a staple food for billions, our research aims to demonstrate the applicability of phenomic selection compared to genomic selection. By investigating the influence of various factors on phenomic prediction accuracy (training population size, incorporation of multiple environment information, consideration of genotype x environment effects in the prediction models), we are contributing to the optimization of this novel breeding method, which could potentially lead to significant improvements in agricultural productivity and food security.

plant biology↗

bioRxiv2023

Human HPSE2 gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome.

Rare early onset lower urinary tract disorders include defects of functional maturation of the bladder. Current treatments do not target the primary pathobiology of these diseases. Some have a monogenic basis, such as urofacial, or Ochoa, syndrome (UFS). Here, the bladder does not empty fully because of incomplete relaxation of its outflow tract, and subsequent urosepsis can cause kidney failure. UFS is associated with biallelic variants of HPSE2, encoding heparanase-2. This protein is detected in pelvic ganglia, autonomic relay stations that innervate the bladder and control voiding. Bladder outflow tracts of Hpse2 mutant mice display impaired neurogenic relaxation. We hypothesized that HPSE2 gene transfer soon after birth would ameliorate this defect and explored an adeno-associated viral (AAV) vector-based approach. AAV9/HPSE2, carrying human HPSE2 driven by CAG, was administered intravenously into neonatal mice. In the third postnatal week, transgene transduction and expression were sought, and ex vivo myography was undertaken to measure bladder function. In mice administered AAV9/HPSE2, the viral genome was detected in pelvic ganglia. Human HPSE2 was expressed and heparanase-2 became detectable in pelvic ganglia of treated mutant mice. On autopsy, wild-type mice had empty bladders whereas bladders were uniformly distended in mutant mice, a defect ameliorated by AAV9/HPSE2 treatment. Therapeutically, AAV9/HPSE2 significantly ameliorated impaired neurogenic relaxation of Hpse2 mutant bladder outflow tracts. Impaired neurogenic contractility of mutant detrusor smooth muscle was also significantly improved. These results constitute first steps towards curing UFS, a clinically devastating genetic disease featuring a bladder autonomic neuropathy. SummaryIn the first gene therapy for genetic bladder disease, we cured autonomic neurons using AAV-mediated gene delivery in a mouse model of urofacial syndrome.

neuroscience↗

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

Genome of the parasitoid wasp Dinocampus coccinellae reveals extensive duplications, accelerated evolution, and independent origins of thelytokous parthenogeny and solitary behavior

Dinocampus coccinellae (Hymenoptera: Braconidae) is a generalist parasitoid wasp that parasitizes >50 species of predatory lady beetles (Coleoptera: Coccinellidae), with thelytokous parthenogeny as its primary mode of reproduction. Here we present the first high quality genome of D. coccinellae using a combination of short and long read sequencing technologies, followed by assembly and scaffolding of chromosomal segments using Chicago+ HiC technologies. We also present a first-pass ab initio genome annotation, and resolve timings of divergence and evolution of (1) solitary behavior vs eusociality, (2) arrhenotokous vs thelytokous parthenogenesis, and (3) rates of gene loss and gain among Hymenopteran lineages. Our study finds (1) at least two independent origins of eusociality and solitary behavior among Hymenoptera, (2) two independent origins of thelytokous parthenogenesis from ancestral arrhenotoky, and (3) accelerated rates of gene duplications, loss, and gain along the lineages leading to D. coccinellae. Our work both affirms the ancient divergence of Braconid wasps from ancestral Hymenopterans and accelerated rates of evolution in response to adaptations to novel hosts, including polyDNA viral co-evolution.

genomics↗

bioRxiv2020

Crop-photoperiodism model 2.0 for the panicle-initiation date of sorghum and rice that includes daily changes in sunrise and sunset times

Background and AimsDaylength determines flowering dates. However, questions remain regarding flowering dates in the natural environment, such as the synchronous flowering of plants sown simultaneously at highly contrasting latitudes. The daily change in sunrise and sunset times is the cue for the flowering of trees and for the synchronisation moulting in birds at the equator. Sunrise and sunset also synchronise the cell circadian clock, which is involved in the regulation of flowering. The goal of this study was to update the photoperiodism model with knowledge acquired since its conception. MethodsA large dataset was gathered, including four 2-year series of monthly sowings of 28 sorghum varieties in Mali and two 1-year series of monthly sowings of eight rice varieties in the Philippines to compare with previously published monthly sowings in Japan and Malaysia, and data from sorghum breeders in France, Nicaragua, and Colombia. An additive linear model of the duration in days to panicle initiation (PI) using day length and daily changes in sunrise and sunset times was implemented. Key ResultsSimultaneous with the phyllochron, the duration to PI of field crops acclimated to the mean temperature at seedling emergence within the usual range of mean cropping temperatures. A unique additive linear model combining daylength and daily changes in sunrise and sunset hours was accurately fitted for any type of response in the duration to PI to the sowing date without any temperature input. Once calibrated on a complete and an incomplete monthly sowing series at two tropical latitudes, the model accurately predicted the duration to PI of the concerned varieties from the equatorial to the temperate zone. ConclusionsThe results of the updated photoperiodism model strongly supported the hypothesis that photoperiodism could be a combined response to day length and daily changes in sunrise and sunset times.

plant biology↗

bioRxiv2019

Lack of phenotypic variation in larval utilization of pea aphids in populations of the ladybeetle Hippodamia convergens

The convergent lady beetle (Hippodamia convergens) is a generalist natural enemy that is utilized extensively in augmentative biological control across the United States. Recent studies have pointed to both genetic and phenotypic differences in Western (California) versus Eastern (Kansas) populations of the species. Here we investigate (1) genetic population structure, and (2) phenotypic differences in the utilization of pea aphids at temperatures that resemble the Western United States in (a) Eastern versus Western populations, (b) F1 Eastern X Western hybrids versus their progenitor populations, and investigate the effects of interaction between (c) Eastern and Western populations. We found no differences in final pupal weight, or the net weight gain ratio through larval development from the third instar to pupal stage, despite genetic population structure. Our study points towards plastic response and effectiveness in feeding phenotypes of Eastern and Western populations of H. convergens, and the absence of hybrid vigor and heterozygote advantages in hybrids.

ecology↗

bioRxiv2018

Interleukin-6 Receptor Signalling and Abdominal Aortic Aneurysm Growth Rates

BackgroundThe Asp358Ala variant (rs2228145; A>C) in the interleukin-6 receptor (IL6R) gene has been implicated in the development of abdominal aortic aneurysms (AAAs), but its effect on AAA growth over time is not known. We aimed to investigate the clinical association between the IL6R-Asp358Ala variant and AAA growth, and to assess the effect of blocking the IL-6 signalling pathway in mouse models of aneurysm rupture.\n\nMethodUsing data from 2,863 participants with AAA from nine prospective cohorts, age- and sex-adjusted mixed-effects linear regression models were used to estimate the association between the IL6R-Asp358Ala variant and annual change in AAA diameter (mm/year). In a series of complementary randomised trials in mice, the effect of blocking the IL-6 signalling pathways was assessed on plasma biomarkers, systolic blood pressure, aneurysm diameter and time to aortic rupture and death.\n\nResultsAfter adjusting for age and sex, baseline aneurysm size was 0.55mm (95% confidence interval [CI]: 0.13, 0.98mm) smaller per copy of the minor allele [C] of the Asp358Ala variant. There was no evidence of a reduction in AAA growth rate (change in growth=-0.06mm per year [-0.18, 0.06] per copy of the minor allele). In two mouse models of AAA, selective blockage of the IL-6 trans-signalling pathway, but not combined blockage of both, the classical and trans-signalling pathways, was associated with improved survival (p<0.05).\n\nConclusionsOur proof-of-principle data are compatible with the concept that IL-6 trans-signalling is relevant to AAA growth, encouraging larger-scale evaluation of this hypothesis.

genetics↗