Biology subjects

Faul, C.

Publications and source records attributed to Faul, C..

3 recordsLinked to original sources

bioRxiv2025

Myeloid FtH Regulates Macrophage Response to Kidney Injury by Modulating Snca and Ferroptosis

This study explored the role of myeloid ferritin heavy chain (FtH) in coordinating kidney iron trafficking in health and disease. Synuclein- (Snca) was the sole iron-binding protein upregulated in response to myeloid FtH deletion (FtH{Delta}/{Delta}). Following kidney injury, FtH{Delta}/{Delta} mice showed worsened kidney function. Transcriptome analysis revealed coupling of FtH deficiency with ferroptosis activation, a regulated cell death associated with iron accumulation. Adverse effects of ferroptosis were evidenced by upregulation of ferroptosis-related genes, increased oxidative stress markers, and significant iron deposition in kidney tissues. This iron buildup in FtH{Delta}/{Delta} kidneys stemmed from macrophage reprogramming into an iron-recycling phenotype, driven by Spic induction. Mechanistically, we establish that monomeric Snca functions as a ferrireductase catalyst, intensifying oxidative stress and triggering ferroptosis. Additionally, Snca accumulates in kidney diseases distinguished by leukocyte expansion across species. These findings position myeloid FtH as a pivotal orchestrator of the FtH-Snca-Spic axis driving macrophage reprogramming and kidney injury. HighlightsO_LIMyeloid FtH deficiency drives kidney injury via activation of ferroptosis C_LIO_LIM{Phi} FtH deficiency induces Snca, linking iron dysregulation to M{Phi} function and response to kidney injury C_LIO_LIFerrireductase activity of monomeric Snca augments oxidative stress, promoting lipid peroxidation and ferroptosis C_LI In briefM{Phi} FtH modulates Snca and Spic to coordinate the injury response, linking iron trafficking to ferroptosis-induced kidney injury

pathology↗

bioRxiv2021

Hyperphosphatemia increases inflammation to exacerbate anemia and skeletal muscle wasting independently of FGF23-FGFR4 signaling

Elevations in plasma phosphate concentrations (hyperphosphatemia) occur in chronic kidney disease (CKD), in certain genetic disorders, and following the intake of a phosphate-rich diet. Whether hyperphosphatemia and/or associated changes in metabolic regulators, including elevations of fibroblast growth factor 23 (FGF23) directly contribute to specific complications of CKD is uncertain. Here we report that similar to patients with CKD, mice with adenine-induced CKD develop inflammation, anemia and skeletal muscle wasting. These complications are also observed in mice fed high phosphate diet even without CKD. Ablation of pathologic FGF23- FGFR4 signaling did not protect mice on an increased phosphate diet or mice with adenine- induced CKD from these sequelae. However, low phosphate diet ameliorated anemia and skeletal muscle wasting in a genetic mouse model of CKD. Our mechanistic in vitro studies indicate that phosphate elevations induce inflammatory signaling and increase hepcidin expression in hepatocytes, a potential causative link between hyperphosphatemia, anemia and skeletal muscle dysfunction. Our study suggests that high phosphate intake, as caused by the consumption of processed food, may have harmful effects irrespective of pre-existing kidney injury, supporting not only the clinical utility of treating hyperphosphatemia in CKD patients but also arguing for limiting phosphate intake in healthy individuals.

cell biology↗

bioRxiv2021

FGF21-FGFR4 signaling in cardiac myocytes promotes concentric cardiac hypertrophy in mouse models of diabetes

Fibroblast growth factor (FGF) 21, a hormone that increases insulin sensitivity, has shown promise as a therapeutic agent to improve metabolic dysregulation. Here we report that FGF21 directly targets cardiac myocytes by binding {beta}-klotho and FGF receptor (FGFR) 4. In combination with high glucose, FGF21 induces cardiac myocyte growth in width mediated by extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. While short-term FGF21 elevation can be cardio-protective, we find that in type 2 diabetes (T2D) in mice, where serum FGF21 levels are elevated, FGFR4 activation induces concentric cardiac hypertrophy. As T2D patients are at risk for heart failure with preserved ejection fraction (HFpEF), we propose that induction of concentric hypertrophy by elevated FGF21-FGFR4 signaling constitutes a novel mechanism promoting T2D-associated HFpEF and that FGFR4 blockade might serve as a cardio-protective therapy in T2D. In addition, potential adverse cardiac effects of FGF21 mimetics currently in clinical trials should be investigated.

molecular biology↗