New Insights in the Contribution of Voltage-Gated Nav Channels to Rat Aorta Contraction

BACKGROUND: Despite increasing evidence for the presence of voltage-gated Na(+) channels (Na(v)) isoforms and measurements of Na(v) channel currents with the patch-clamp technique in arterial myocytes, no information is available to date as to whether or not Na(v) channels play a functional role in arteries. The aim of the present work was to look for a physiological role of Na(v) channels in the control of rat aortic contraction. METHODOLOGY/PRINCIPAL FINDINGS: Na(v) channels were detected in the aortic media by Western blot analysis and double immunofluorescence labeling for Na(v) channels and smooth muscle alpha-actin using specific antibodies. In parallel, using real time RT-PCR, we identified three Na(v) transcripts: Na(v)1.2, Na(v)1.3, and Na(v)1.5. Only the Na(v)1.2 isoform was found in the intact media and in freshly isolated myocytes excluding contamination by other cell types. Using the specific Na(v) channel agonist veratridine and antagonist tetrodotoxin (TTX), we unmasked a contribution of these channels in the response to the depolarizing agent KCl on rat aortic isometric tension recorded from endothelium-denuded aortic rings. Experimental conditions excluded a contribution of Na(v) channels from the perivascular sympathetic nerve terminals. Addition of low concentrations of KCl (2-10 mM), which induced moderate membrane depolarization (e.g., from -55.9+/-1.4 mV to -45.9+/-1.2 mV at 10 mmol/L as measured with microelectrodes), triggered a contraction potentiated by veratridine (100 microM) and blocked by TTX (1 microM). KB-R7943, an inhibitor of the reverse mode of the Na(+)/Ca(2+) exchanger, mimicked the effect of TTX and had no additive effect in presence of TTX. CONCLUSIONS/SIGNIFICANCE: These results define a new role for Na(v) channels in arterial physiology, and suggest that the TTX-sensitive Na(v)1.2 isoform, together with the Na(+)/Ca(2+) exchanger, contributes to the contractile response of aortic myocytes at physiological range of membrane depolarization

State of the art and the future of microbiome-based biomarkers:a multidisciplinary Delphi consensus

Although microbiome signatures have been identified in various contexts (ie, pathogenesis of non-communicable diseases and treatment response), qualified microbiome-based biomarkers are currently not in use in clinical practice. The Human Microbiome Action consortium initiated a Delphi survey to establish a consensus on the needs, challenges, and limitations in developing qualified microbiome-based biomarkers. The questionnaire was developed by a scientific committee via literature review and expert interviews. To ensure broad applicability of the results, 307 experts were invited to participate; 114 of them responded to the first round of the survey, 93 of whom completed the second and final round as well. The survey highlighted the experts’ confidence in the potential of microbiome-based biomarkers for several indications or pathologies. The paucity of validated analytical methods appears to be the principal factor hindering the qualification of these biomarkers. The survey also showed that clinical implementation of these biomarkers would only be possible if kitted and validated molecular assays with simple interpretation are developed. This initiative serves as a foundation for designing and implementing public-private collaborative projects to overcome the challenges and promote clinical application of microbiome-based biomarkers.</p

Impact cardiaque, vasculaire et rénal d'une consommation sodée excessive chez le rat. Traitement pharmacologique des modifications structurales et fonctionnelles

Le but de ce travail est d'étudier l'impact de l'augmentation précoce (sevrage) et de longue durée (5 mois) de l'apport sodé (HS2 ou 8% NaCI), et d'approcher pharmacologiquement les mécanismes. Dans ce modèle on observe le développement d'une hypertrophie cardiaque et vasculaire, et une diminution du taux de filtration glomérulaire, sans fibrose. l'aldostérone et ET1 semblent participer au maintien des altérations dans le régime sévère. Le SRAA tissulaire semble impliqué dans le régime modéré. Le régime sévère est associé à une augmentation du CA2+ dans cellule musculaire lisse, et à l'activité accrue du système NO (augmentation de la sensibilité au NO et au GMPc, activité majorée des BKCa). Ces modifications représenteraient un mécanisme compensateur permettant de maintenir normal le niveau de pression artériellePARIS5-BU-Necker : Fermée (751152101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

CBP and p300 are essential for renin cell identity and morphological integrity of the kidney

The mechanisms that govern the identity of renin cells are not well understood. We and others have identified cAMP as an important pathway in the regulation of renin synthesis and release. Recently, experiments in cells from the renin lineage led us to propose that acquisition and maintenance of renin cell identity are mediated by cAMP and histone acetylation at the cAMP responsive element (CRE) of the renin gene. Ultimately, the transcriptional effects of cAMP depend on binding of the appropriate transcription factors to CRE. It has been suggested that access of transcription factors to this region of the promoter is facilitated by the coactivators CREB-binding protein (CBP) and p300, which possess histone acetyltransferase activity and may be, in turn, responsible for the remodeling of chromatin underlying expression of the renin gene. We hypothesized that CBP and p300 are therefore required for expression of the renin gene and maintenance of the renin cell. Because mice homozygous for the deletion of CBP or p300 die before kidney organogenesis begins, no data on kidney or juxtaglomerular cell development in these mice are available. Therefore, to define the role of these histone acetyltransferases in renin cell identity in vivo, we used a conditional deletion approach, in which floxed CBP and p300 mice were crossed with mice expressing cre recombinase in renin cells. Results show that the histone acetyltransferases CBP and p300 are necessary for maintenance of renin cell identity and structural integrity of the kidney

Gut–Kidney Axis Investigations in Animal Models of Chronic Kidney Disease

International audienceChronic kidney disease (CKD) is an incurable disease in which renal function gradually declines, resulting in no noticeable symptoms during the early stages and a life-threatening disorder in the latest stage. The changes that accompany renal failure are likely to influence the gut microbiota, or the ecosystem of micro-organisms resident in the intestine. Altered gut microbiota can display metabolic changes and become harmful to the host. To study the gut–kidney axis in vivo, animal models should ideally reproduce the disorders affecting both the host and the gut microbiota. Murine models of CKD, but not dog, manifest slowed gut transit, similarly to patient. Animal models of CKD also reproduce altered intestinal barrier function, as well as the resulting leaky gut syndrome and bacterial translocation. CKD animal models replicate metabolic but not compositional changes in the gut microbiota. Researchers investigating the gut–kidney axis should pay attention to the selection of the animal model (disease induction method, species) and the setting of the experimental design (control group, sterilization method, individually ventilated cages) that have been shown to influence gut microbiota