Biology subjects

Moor, M. B.

Publications and source records attributed to Moor, M. B..

7 recordsLinked to original sources

bioRxiv2026

Population genetics meets precision-cut kidney slices: Nephrotoxicity modelled ex vivo in the founder strains of the BXD mouse consortium

Acute kidney injury (AKI) affects millions of patients annually and is associated with high morbidity and mortality, to date no curative treatment exists. Drug-induced nephrotoxicity accounts for up to 25% of AKI cases, but individual susceptibility remains hard to predict. While genetic factors are suspected to play a part in this variability, the pharmacogenomics of nephrotoxin-induced kidney injury remain largely unknown. To investigate genetically determined susceptibility, we used precision-cut kidney slices (PCKS) from the two founder strains of the BXD mouse consortium, C57BL/6J and DBA/2J. PCKS preserves tissue architecture and cell-cell interaction, allowing close experimental control while maintaining the renal microenvironment. Slices were exposed to cyclosporine A (80 nM for 6h, 20nM for 24h and 48h) and Tunicamycin (1 {micro}M for 6h and for 24h) as well as normoxia (4{degrees}C for 20h) and hyperoxia (4{degrees}C for 20h and 4h in incubator). Slices were then analysed using histopathological scoring, TUNEL staining, ATP quantification and bulk RNA sequencing. We found that the main source of variation was experimental duration. Nevertheless, a subtle difference between the strains could be observed for both cyclosporine A and Tunicamycin, with DBA/2J showing a stronger response to nephrotoxic stress, including lower ATP levels, higher proportion of apoptotic cells and a more pronounced transcriptomic response. For both strains, normoxia was the least harmful condition. These findings support the hypothesis that the BXD founder strains differ in their susceptibility to nephrotoxic kidney injury and support the use of PCKS as a relevant ex vivo model for studying early renal stress response. This provides the foundation to extend this approach to a broader spectrum of the BXD population to identify genetic loci and candidate genes involved in genetic susceptibility to nephrotoxins.

pharmacology and toxicology↗

bioRxiv2025

Genetic dissection of tissue composition in genetically diverse mouse populations

BackgroundSingle-cell RNAseq data can be harnessed to infer cell-type compositions from spatial or bulk transcriptomes, providing greater biological context underlying systemic tissue or organ dynamics. Here, we used a transcriptome-based systems genetics approach to assess biological factors that influence the cellular composition of tissues, including sex, age and genetic variation in two multiparental mouse resource populations derived from the same 8 parental strains. MethodsWe leveraged publicly available bulk RNAseq data from kidney, heart and bone from 188 Diversity Outbred (DO) mice and male/female pairs from 58 inbred strains of the Collaborative Cross (CC). DO mice were aged 6, 12 or 18 months. We used single-cell RNAseq data from healthy C57BL/6 mice as reference for cell-type decomposition of bulk transcriptomes. We tested for differences in cell type composition based on age and sex. We then performed genetic analysis on the cell-type composition phenotypes, estimating the heritability of cell composition levels, mapping cell composition quantitative trait loci (ccQTL), and assessing candidate gene intermediates of ccQTL based on a genetic mediation approach and support in the literature. ResultsThe heritability of cell-type compositions differed between the inbred CC and outbred DO. Contrasting this, we observed strong and consistent sex differences between the CC and DO. For example, we observed consistency in renal proximal tubule segment 3 (higher in males), T cell abundance in kidney (higher in females), ventricular cardiomyocyte (higher in males) and endocardial cells (higher in females). DO mice exhibited increased levels B and T cells with age, representing an age-related increase in overall renal immune cell content. In heart, DO mice showed decreased ventricular cardiomyocyte composition and increasing endocardial cell content with age. In bone from DO mice, vascular endothelial cells decreased with age and bone marrow stromal cells increased with age. Genome-wide association yielded several cell composition QTLs (ccQTLs) in the three tissues, likely related to known biological phenomena. These include a ccQTL for cardiac fibroblasts in the CC that contains the Frg2 gene family and fibroblast growth factor inhibitor Spry2, and a bone vascular endothelial cell ccQTL in the DO that encompasses 10 genes encoding members of the S100a protein family. In addition, our analysis revealed several ccQTLs for different renal tubular segments, immune cell content, and approximately two thirds of cardiac cell types. ConclusionWe establish a role for transcriptome-inferred cellular states or composition for QTL mapping, which adds further utility to existing resources. Furthermore, differences in heritability and QTL between the CC and DO highlight how variation in allele frequencies and inbred vs outbred genetic backgrounds allow for population-specific genetic effects to be discovered. Several of the renal tubular segment and cardiac cell ccQTLs have narrow confidence regions with the potential to harbor novel biological insight. Overall, we propose that our ccQTL mapping approach can be applied systematically across readily available genetic resource transcriptomes to enable new biological discoveries.

genetics↗

bioRxiv2025

The renal response to FGF23 shifts from phosphaturia towards inflammation in murine kidney disease models

BackgroundFGF23 excess is associated with morbidity and mortality, but the role of excessive circulating FGF23 concentrations as a mere biomarker or causative factor of pathology is controversial. Here, we investigated the consequences of FGF23 excess in kidney disease. MethodsThis study used three independent disease models: i) anti-glomerular basement membrane (Anti-GBM) disease in male C57BL/6 mice, ii) Adriamycin (doxorubicin)-induced nephropathy in female BALB/c mice, and iii) male DBA/2J mice fed an adenine-containing diet. Anti-GBM and Adriamycin mice and matched control mice received intravenous injections of recombinant FGF23 1{micro}g or vehicle for six consecutive days (Anti-GBM) or once (Adriamycin model), with dissection 24h after the last injection. Adenine mice underwent organ harvesting after 15 weeks to establish ex vivo precision-cut kidney slices (PCKS) and 24h treatment with recombinant FGF23 or vehicle. In addition to histological and biochemical profiling, we assessed serum cytokines, biochemistry and renal transcriptomes and histology of mice and patients with IgA nephropathy. RNAseq data and published transcriptomes underwent gene set enrichment, bulk ligand-receptor interaction analysis and cell-type decomposition. ResultsMice with Anti-GBM disease showed decreased glomerular filtration rate, albuminuria and renal tubular casts. FGF23 treatment increased phosphaturia, but also circulating soluble TNF receptor-1. Renal transcriptomes revealed FGF23-driven proinflammatory transcriptional signatures in murine Anti-GBM and also adverse Vcam1, Pdgfrb and chemokine ligand-receptor signaling in Anti-GBM but not in healthy mice. FGF23 increased transcriptome-inferred renal macrophage content in Anti-GBM mice. Findings were confirmed by immunofluorescence. In Adriamycin-induced nephropathy and in PCKS from the adenine nephropathy model, a short-term FGF23 excess caused expression of proinflammatory transcripts. Finally, human data revealed associations between histopathological or transcriptome-inferred renal immune cell infiltration and circulating FGF23 concentrations. ConclusionFGF23-driven patterns of proinflammatory gene and protein expression or leukocyte overabundance in the kidney were observed in several different models or states of FGF23 excess. The present data provide evidence that excess FGF23 directly drives inflammation in kidney disease and may serve as a therapeutic target.

molecular biology↗

bioRxiv2024

Fgf23 expression increases atherosclerotic plaque burden in male ApoE deficient mice

IntroductionComponents of both the innate and adaptive immune system impact on arterial walls in atherosclerosis. Fibroblast growth factor-23 (FGF23) is a phosphate regulating hormone linked to cardiovascular disease (CVD) in patients with and without chronic renal disease. However, it remains controversial whether FGF23 is merely a biomarker or contributes to CVD. Here, we overexpressed FGF23 in ApoE-/- mice to delineate the role of FGF23 in atherogenesis. Methods and Results10-week old ApoE-/- mice received a hydrodynamic tail vein with a plasmid encoding for Fgf23, and were sacrificed 10 weeks later. Fgf23 concentrations increased more than 400-fold in the Fgf23 treated group, remaining high throughout the experiment. Mice in the Fgf23 group developed hypophosphatemia, secondary hyperparathyroidism and a moderate increase in plasma creatinine concentrations. Male ApoE-/- mice exposed to high Fgf23 developed larger atherosclerotic lesions compared to controls, in two different locations of aorta, whereas no differences in plaque burden were seen between female ApoE-/- mice and controls. Serum IL-6 concentrations were increased in the Fgf23 group, associated with a vascular inflammatory response of recruited macrophages and neutrophils, and with a shift of CD4+ T effector cells from Th1 to Th17 and migration of lymphocytes to the spleen. ConclusionFgf23 increases the atherosclerotic burden in male ApoE-/- mice and alters both the innate immune system and T cell subpopulations, generating an inflammatory environment that may promote adverse clinical outcomes associated with Fgf23 excess.

physiology↗

bioRxiv2024

Comparative analysis of kidney transplantation modeled using precision-cut kidney slices and kidney transplantation in pigs

Kidney transplants are at risk for so far unavoidable ischemia-reperfusion injury. Several experimental kidney transplantation models are available to study this injury, but all have their own limitations. Here, we describe precision-cut kidney slices (PCKS) as a novel model of kidney ischemia-reperfusion injury in comparison with pig and human kidney transplantation. Following bilateral nephrectomy in pigs, we applied warm ischemia (1h), cold ischemia (20h) and a reperfusion period (4h) to one whole kidney undergoing transplantation to a recipient pig and, in parallel, established PCKS undergoing ischemia and modeled reperfusion. Histopathological assessment revealed the presence of some but not all morphological features of tubular injury in PCKS as seen in pig kidney transplantation. RNAseq demonstrated that the majority of changes occurred after reperfusion only, with a partial overlap between PCKS and kidney transplantation, with some differences in transcriptional response attributable to systemic inflammatory responses and immune cell migration. Comparison of PCKS and pig kidney transplantation with RNAseq data from human kidney biopsies by gene set enrichment analysis revealed that both PCKS and pig kidney transplantation reproduced the post-reperfusion pattern of human kidney transplantation. In contrast, only post-cold ischemia PCKS and pig kidney partially resembled the gene set of human acute kidney injury. Overall, the present study established that a PCKS protocol can model kidney transplantation and its reperfusion-related damage on a histological and a transcriptomic level. PCKS may thus expand the toolbox for developing novel therapeutic strategies against ischemia-reperfusion injury.

pathology↗

bioRxiv2020

Redox protein Memo1 coordinates FGF23-driven signaling and small Rho-GTPases in the mouse kidney

Memo1 deletion in mice causes premature aging and an unbalanced metabolism partially resembling Fgf23 and Klotho loss-of-function animals. We report a role for Memos redox function in renal FGF23-Klotho signaling using mice with postnatally induced Memo deficiency in the whole body (cKO). Memo cKO mice showed impaired FGF23-driven renal ERK phosphorylation and transcriptional responses. FGF23 actions involved activation of oxidation-sensitive protein phosphotyrosyl phosphatases (PTP) in the kidney. Redox proteomics revealed excessive thiols of Rho-GDP dissociation inhibitor 1 (Rho-GDI1) in Memo cKO, and we detected a functional interaction between Memos redox function and oxidation at Rho-GDI1 Cys79. In isolated cellular systems, Rho-GDI1 did not directly affect FGF23-driven cell signaling, but we detected disturbed Rho-GDI1 dependent small Rho-GTPase protein abundance and activity in the kidney of Memo cKO mice. Collectively, this study reveals previously unknown layers in the regulation of renal FGF23 signaling and connects Memo with the network of small Rho-GTPases.

biochemistry↗

bioRxiv2020

Memo1 gene expression in kidney and bone is unaffected by dietary mineral load and calciotropic hormones

Mediator of Cell Motility 1 (MEMO1) is an ubiquitously expressed modulator of cellular responses to growth factors including FGF23 signaling, and Memo1-deficient mice share some phenotypic traits with Fgf23- or Klotho-deficient mouse models. Here, we tested whether Memo1 gene expression is regulated by calciotropic hormones or by changing the dietary mineral load. MLO-Y4 osteocyte-like cells were cultured and treated with 1,25(OH)2-vitamin D3. Wildtype C57BL/6N mice underwent treatments with 1,25(OH)2-vitamin D3, parathyroid hormone (PTH), 17{beta}-estradiol or vehicle. Other cohorts of C57BL/6N mice were fed diets varying in calcium or phosphate content. Expression of Memo1 and control genes was assessed by qPCR. 1,25(OH)2-vitamin D3 caused an acute decrease in Memo1 transcript levels in vitro, but not in vivo. None of the hormones tested had an influence on Memo1 transcripts, whereas the assessed control genes reacted the expected way. Dietary interventions with calcium and phosphate did not affect Memo1 transcripts but altered the chosen control genes expression. We observed that Memo1 was not regulated by calciotropic hormones or change in mineral load, suggesting major differences between the regulation and physiological roles of Klotho, Fgf23 and Memo1.

physiology↗