bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.03.10.642360

Placenta hIGF1 nanoparticle treatment in guinea pigs mitigates fetal sex dependent FGR-associated effects on kidney structure and blood pressure-related signaling pathways

Davenport, B.·Williams, A.·Regnault, T.·Jones, H.·Wilson, R.
View original source ↗Export metadata ↓

Abstract

Fetal development in an adverse in utero environment significantly increases the risk of hypertension and cardiovascular disease. The kidneys play a pivotal role in the regulation of blood pressure and cardiovascular function, and perturbations in kidney structure and molecular profile are often demonstrated in offspring born fetal growth restricted (FGR). The aim of this study was to determine whether improving the in utero fetal growth environment with a placental nanoparticle gene therapy would ameliorate FGR-associated dysregulation of fetal kidney development. Using the guinea pig maternal nutrient restriction (MNR) model, we improved placenta efficiency and fetal weight following three placental administrations of a non-viral polymer-based nanoparticle gene therapy from mid-pregnancy (gestational day 35) until gestational day 52. The nanoparticle gene therapy transiently increased expression of human insulin-like growth factor 1 (hIGF1) in placenta trophoblast. Fetal kidney tissue was collected near-term at gestational day 60. Differences in kidney structure, glomeruli size and gene expression of extracellular matrix (ECM) remodeling and blood pressure regulation-related factors were demonstrated in sham-treated FGR fetuses but not observed in FGR fetuses who received placental hIGF1 nanoparticle treatment. We speculate that mitigating the FGR-associated changes in kidney architecture and molecular profiles might confer protection against increased susceptibility to aberrant kidney physiology in later-life. Overall, this work opens avenues for future research to assess the long-term impact of the placental hIGF1 nanoparticle gene therapy on cardiovascular function in offspring.

Source connections

Explore related subjects

physiologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Davenport, B., Williams, A., Regnault, T., Jones, H., Wilson, R.. 2025-03-13. Placenta hIGF1 nanoparticle treatment in guinea pigs mitigates fetal sex dependent FGR-associated effects on kidney structure and blood pressure-related signaling pathways. https://doi.org/10.1101/2025.03.10.642360

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Hypothalamic Farnesoid X Receptor deficiency alters energy balance by modulating hepatic glucose production and adipose tissue metabolism through central insulin signaling.

Objectives: The bile acid nuclear receptor Farnesoid X Receptor (FXR, NR1H4) is a major regulator of metabolism and energy homeostasis in peripheral organs. It modulates bile acid, glucose, and lipid metabolism, as well as fat mass and body weight. However, FXR is also expressed in the brain, particularly in the hypothalamus, a key center for the regulation of energy homeostasis. Although one study has demonstrated a role for brain FXR activation in energy balance, its specific hypothalamic role is still unknown. Here, we examined the role of FXR in the mediobasal hypothalamus in the regulation of energy balance. Methods: We used a genetic approach combined with metabolic phenotyping to determine the effect of FXR invalidation in the mediobasal hypothalamus on metabolic parameters involved in the central regulation of energy homeostasis. Results: Our results demonstrate that hypothalamic FXR deficiency induces a positive energy balance, resulting in a reduction in energy expenditure due to alterations in glucose metabolism accompanied by structural changes in white adipose tissues. Conclusion: This study uncovers a previously unrecognized role for hypothalamic FXR in the central homeostatic control of energy balance, providing new insights into its contribution to peripheral glucose metabolism and adipose tissue structural remodeling.

physiology↗
bioRxiv2026

Rad and Phospholamban are Key Drivers of the Ventricular Adrenergic Response and Stress-Induced Arrhythmia

The adrenergic response is a fundamental mechanism that regulates heart rate (chronotropy), cardiac contractility (inotropy) and relaxation (lusitropy). Adrenergic stress is also a recognized trigger of arrhythmia in disease. Yet, our understanding of the underlying molecular basis remains incomplete. Protein kinase A (PKA) and the calcium/calmodulin-dependent kinase II (CaMKII) phosphorylate multiple targets proposed to participate in the adrenergic response, including the GTP-binding protein Rad, phospholamban (PLB) and ryanodine receptor 2 (RyR2). Here we demonstrate that phosphorylation of both Rad and PLB is necessary for inotropy and lusitropy. We show that changes in cardiac contractility and relaxation are primarily dependent on intracellular calcium handling. Finally, we report that Rad and PLB control stress-induced arrhythmogenesis, despite the phosphorylation of other pro-arrhythmic targets. We have identified the essential molecular components of the adrenergic response, resolving a long-standing debate in cardiac excitation-contraction coupling and refining current models of sympathetic regulation in health and disease.

physiology↗
bioRxiv2026

Light-cycle time-restricted feeding remodels a hidden layer of the cardiac transcriptome through sex-specific transcript switching

Light-cycle time-restricted feeding disrupts daily cardiovascular and thermoregulatory rhythms, but the molecular effects of light-cycle time-restricted feeding on the heart have been measured only at the level of total gene expression. We used Oxford Nanopore long-read RNA sequencing to resolve the full-length ventricular transcriptome from male and female mice under ad libitum feeding or light-cycle time-restricted feeding across the 24-hour cycle. Greater than 20% of cardiac transcripts represent unannotated variants of known genes absent from the current GENCODE reference annotation. Light-cycle time-restricted feeding reorganizes transcript usage across hundreds of genes, including genes encoding splicing regulators, largely without changing total gene expression. The genes affected are sex-specific, with fewer than 2% of changes shared at the gene, transcript, and transcript-usage levels. We show that transcript-level regulation is a previously underrecognized component of the cardiac response to altered feeding behavior, undetected by conventional short-read approaches.

physiology↗