口丸 高弘

Fibroblast growth factor-23 (FGF23) is a bone-derived hormone that promotes urinary phosphate excretion in response to phosphate loading. While essential for phosphate homeostasis, elevated FGF23 increases phosphate concentration in the renal tubular fluid, promoting calcium-phosphate crystal formation and tubular injury. Here we show that bone resorption mobilizes phosphate into the circulation and mimics the pathophysiology of dietary phosphate loading. Enhanced bone resorption, induced by soluble receptor activator of NF-κB ligand (sRANKL) administration or microgravity exposure on the International Space Station, increased circulating FGF23 levels and caused renal tubular injury in mice. Pre-treatment with bisphosphonate, an inducer of osteoclast apoptosis, prevented sRANKL-induced increases in FGF23 and tubular damage. These findings suggest that bone mineral loss may contribute to renal tubular injury in clinical settings, including immobilization, osteoporosis, and chronic kidney disease-mineral bone disorder.

The ring finger protein 213 (RNF213) gene, identified in 2011 as a susceptibility gene for moyamoya disease (MMD), has since been recognized as a key factor in a broader spectrum of vascular disorders. The p.R4810K mutation in RNF213 is particularly common among Japanese MMD patients, although a smaller percentage of healthy individuals also carry the mutation, indicating that environmental factors, alongside genetic predisposition, likely influence disease onset. RNF213, a large E3 ubiquitin ligase, plays essential roles in vascular homeostasis, immune response, and endoplasmic reticulum stress reaction. Its mutation disrupts normal angiogenesis, contributing to abnormal vascular remodeling in conditions such as pulmonary hypertension and coronary artery disease. This review examines the multifaceted role of RNF213 and its p.R4810K mutation in the pathogenesis of MMD and other vascular conditions, collectively referred to as RNF213-associated vascular diseases. While research has begun to clarify the mutation's effects on angiogenesis and the involved pathways, the roles of RNF213 and its mutation in vascular integrity remain unclear. This comprehensive overview underscores the complex interaction between genetic and environmental factors in RNF213-related vascular diseases and calls for further research to elucidate these mechanisms and develop targeted therapeutic interventions.

AIMS: Hypoxia-inducible factor (HIF) signalling influences cardiomyocyte differentiation, maturation, and metabolic adaptation under pathological conditions. HIF-Prolyl hydroxylase domain (HIF-PH) inhibitors, which target this pathway, have been introduced for the treatment of renal anaemia. Their precise effect or safety on cardiac function remains unclear because their pharmacokinetics and distribution are not well-understood. This study aimed to examine HIF signalling activation in adult cardiomyocytes (CMs). METHODS AND RESULTS: We used tamoxifen (TAM)-inducible, CM-specific von Hippel-Lindau (VHL) knockout (VHL-MCM) mice to activate CM HIF signalling. Then we subjected the mice to normal ageing or high-fat diet (HFD) and L-NAME feeding, a murine model of heart failure with preserved ejection fraction (HFpEF). In normal ageing group, there was no difference in the echocardiographic parameters or tissue fibrosis between VHL-MCM and control mice. VHL-MCM mice exhibited significantly increased capillary density and higher expression levels of HIF-target genes (P = 0.0248, two-way ANOVA). Under HFD + L-NAME treatment, VHL-MCM mice showed transient but significantly preserved global longitudinal strain (GLS) at 12 weeks post-TAM injection compared to controls (P = 0.0284, two-way ANOVA). Sirius red staining indicated a trend towards reduced whole-heart and interstitial fibrosis with significant increase in capillary density in VHL-MCM mice. CONCLUSION: Sustained HIF signalling activation in adult CM does not impair the cardiac structure and function in normal ageing process and shows transient yet beneficial effect in murine HFpEF model.

Hypoxia-inducible factor-1α (HIF-1α) plays a crucial role in cellular and tissue adaptation to low oxygen conditions. Although inflammatory stimuli such as lipopolysaccharide (LPS) also increase HIF-1α levels under normoxia, its transcriptional activity and regulatory mechanisms in this context remain unclear. To address this, we performed chromatin immunoprecipitation sequencing and transcriptome analyses in murine macrophages stimulated with either LPS or hypoxia. Both stimuli stabilized HIF-1α protein but via distinct mechanisms: hypoxia acted post-translationally, whereas LPS increased Hif-1α mRNA expression. Genome-wide HIF-1α binding was observed under both conditions; however, only hypoxia induced broad transcriptional activation of target genes, whereas LPS upregulated a restricted set, mostly glycolytic genes. Motif enrichment analysis revealed that hypoxia, but not LPS, promoted cooperative transcription factor engagement, including HIF-1β, ETS, and bZIP family members. Hypoxia also increased H3K27 acetylation at HIF-1α target loci, consistent with a transcriptionally permissive chromatin state. In contrast, LPS led to reduced H3K27ac at noninduced loci, suggesting epigenetic repression. Mechanistically, HIF-1α exhibited a phosphorylation-dependent band shift under hypoxia but not LPS. Although both conditions showed comparable overall phosphorylation levels by Phos-tag analysis, only hypoxia triggered a conformational change, suggesting site-specific phosphorylation linked to transcriptional competence. These findings demonstrate that HIF-1α binding alone is insufficient for gene activation and that phosphorylation and chromatin context determine its transcriptional output in a stimulus-dependent manner.

Hematopoietic stem cells (HSCs) possess the capacity to regenerate the entire hematopoietic system. However, the precise HSC dynamics in the early post-transplantation phase remain an enigma. Clinically, the initial hematopoiesis in the post-transplantation period is critical, necessitating strategies to accelerate hematopoietic recovery. Here, we uncovered the spatiotemporal dynamics of early active hematopoiesis, "hematopoietic cell inflation," using a highly sensitive in vivo imaging system. Hematopoietic cell inflation occurs in three peaks in the spleen after transplantation, with common myeloid progenitors (CMPs), notably characterized by HSC-like signatures, playing a central role. Leveraging these findings, we developed expanded CMPs (exCMPs), which exhibit a gene expression pattern that selectively proliferates in the spleen and promotes hematopoietic expansion. Moreover, universal exCMPs supported early hematopoiesis in allogeneic transplantation. Human universal exCMPs have the potential to be a viable therapeutic enhancement for all HSC transplant patients.