Jelinic, M. | Search bioRxiv

bioRxiv2025

Marginal zone B cells are antigenically activated, infiltrate the kidneys, and exacerbate angiotensin II-dependent hypertension in mice

AimsB cells contribute to the development of hypertension, yet, the specific B cell subsets involved, the mechanism underlying their activation, and the relevance of these responses to human disease remain poorly defined. Methods and resultsWe used single-cell RNA sequencing, single-cell B cell receptor (BCR) VDJ sequencing, and high dimensional flow cytometry to characterise B cell responses in murine angiotensin II-induced hypertension. Chronic angiotensin II infusion in male and female mice increased systolic blood pressure and selectively expanded marginal zone B (MZB) cells, with evidence of antigen-dependent activation, including clonal BCR expansion, enrichment of IGHV1 B cell receptor variants, and increased expression of activation markers (CD69 and Nur77). Intercellular communication analyses revealed enhanced antigen-presentation signalling between MZB and CD8+ T cells in hypertensive mice. Activated MZB-like memory B cells also accumulated in the kidneys of hypertensive mice. Consistent with these findings, multiomic analysis of kidneys from patients with hypertensive chronic kidney disease (CKD) demonstrated an increase in memory B cells with a MZB phenotype and enrichment of antigen-presentation-linked communication with CD8+ T cells. Importantly, hypertensive responses to angiotensin II infusion were significantly blunted in mice lacking MZB cells (BAFF-R-/-). ConclusionOur findings identify MZB cells as a selectively activated, antigen-responsive B cell subset that amplified pathogenic immune responses in murine and human hypertension. By linking subset-specific BCR activation to immune cross-talk and disease causality, this study identifies MZB cells - and the (auto)antigens that activate them - as promising targets for precision immunomodulatory strategies in hypertension.

physiology↗

bioRxiv2025

High-resolution transcriptomic profiling of the aortic cellular landscape during hypertension reveals novel drivers of vascular fibrosis

BackgroundAortic stiffening is a consequence of hypertension and a major contributor to end organ damage. A key driver of aortic stiffening is fibrosis involving the excess production of extracellular matrix (ECM) proteins such as collagen, fibronectin and laminin. The present study aimed to identify the cell types and signalling mechanisms that contribute to aortic fibrosis in hypertension. Methods and ResultsMale C57BL/6 mice (10-12-week-old) were randomly assigned to a 28-day angiotensin II (0.7 mg/kg/day) or vehicle (saline) infusion via osmotic minipump (s.c.). At endpoint, scRNA-seq analysis of 26,196 cells recovered all major aortic cell populations. Among these, fibroblasts exhibited the greatest heterogeneity and shift in gene expression after angiotensin II compared to all other cell types. Gene ontology analyses revealed that after angiotensin II treatment, a particular subcluster of fibroblasts (Fibro-Cthrc1) - characterised by its high expression of Cthrc1 - was especially fibrogenic. Fibro-Cthrc1 cells were nearly undetectable in aortas from vehicle-infused mice. Transcripts relating to ECM remodelling (Thbs2, Cdh11 and Postn) and collagen production (specifically collagen type I, III and V) were more highly enriched in Fibro-Cthrc1 compared to other fibroblasts within hypertensive aortas. Moreover, GO terms corresponding to profibrotic signalling pathways (i.e., cell adhesion, extracellular matrix organisation and collagen fibril organisation) were significantly enriched in Fibro-Cthrc1. Spatial transcriptomics and immunohistochemistry confirmed the presence of Fibro-Cthrc1 in the adventitial layer of angiotensin II-infused but not vehicle-infused mice. Finally, analysis of plasma analytes in approximately 24,000 participants of the UK Biobank collection revealed CTHRC1 to be strongly associated with raised systolic blood pressure and pulse pressure, and a strong predictor of the risk of developing hypertension over a 15-year follow-up. ConclusionOur study identifies a novel fibroblast subcluster, Fibro-Cthrc1, as a potential driver of aortic fibrosis and stiffening in hypertension. This cluster is absent in normotensive aortas, suggesting that targeting Fibro-Cthrc1 therapeutically could prevent aortic fibrosis and its associated hypertensive end-organ damage. Notably, such an approach may avoid compromising physiological extracellular matrix production and vessel integrity. Translational perspectiveAortic stiffening is a hallmark of hypertension resulting from functional (vasoconstriction) and structural (extracellular matrix remodelling) alterations of the vessel wall. While several antihypertensive medications address functional changes, no therapies directly target the causes of the structural remodelling. The therapeutic challenge is to distinguish between physiological and pathological extracellular matrix remodelling. This study identifies a novel highly profibrotic fibroblast cell population (Fibro-Cthrc1) present in aortas from hypertensive, but not normotensive mice. This raises the possibility that Fibro-Cthrc1 may be a key driver of aortic stiffening and a promising future therapeutic target.

physiology↗

bioRxiv2024

Impact of Parental Time-Restricted Feeding on Offspring Metabolic Phenotypic Traits

A substantial body of research elucidates the mechanisms and health advantages associated with intermittent fasting (IF). However, the impact of parental IF on offspring remains unclear. Through an investigation involving four IF and ad libitum combinations of parental mating groups, we demonstrate that parental IF (daily time-restricted feeding) influences offsprings metabolic health indicators in male and female offspring in distinct ways. We found that when both parents are on IF their offspring exhibit protection against the adverse effects of a high-fat, high-sugar, and high-salt diet in a sex-specific manner. This study underscores the potential significance of parental lifestyle modifications involving dietary restriction for the metabolic status of their children and their risk for obesity and diabetes.

genetics↗