In most patients with type 1 xanthinuria caused by mutations in the xanthine dehydrogenase gene (XDH), no clinical complications, except for urinary stones, are observed. In contrast, all Xdh(- / -) mice die due to renal failure before reaching adulthood at 8 weeks of age. Hypoxanthine or xanthine levels become excessive and thus toxic in Xdh(- / -) mice because enhancing the activity of hypoxanthine phosphoribosyl transferase (HPRT), which is an enzyme that uses hypoxanthine as a substrate, slightly increases the life span of these mice. In this study, we targeted the mouse intestinal sodium-dependent nucleobase transporter (SNBT) gene (Slc23a4), which is a pseudogene in humans. Hprt(high)Xdh(- / -)Slc23a4(- / -) mice had a longer life span and reached adulthood. The urinary xanthine excretion of these mice was 20-fold greater than that of patients with type 1 xanthinuria. The urinary hypoxanthine/xanthine ratio of Hprt(high)Xdh(- / -)Slc23a4(- / -) mice was lower than that of patients with type 1 xanthinuria. Hprt(high)Xdh(- / -)Slc23a4(- / -) mice exhibited renal impairment, accompanied by high plasma creatinine levels and anemia. Moreover, female Hprt(high)Xdh(- / -)Slc23a4(- / -) mice produced offspring that did not survive. In conclusion, for the first time, we established that Xdh(- / -) mice survive to adulthood.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1038/s41598-025-87751-9 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Inhibition of vascular smooth muscle cell PERK/ATF4 ER stress signaling protects against abdominal aortic aneurysms.
JCI Insight
January 2025
Section of Vascular Surgery, Department of Surgery, and.
Abdominal aortic aneurysms (AAA) are a life-threatening cardiovascular disease for which there is a lack of effective therapy preventing aortic rupture. During AAA formation, pathological vascular remodeling is driven by vascular smooth muscle cell (VSMC) dysfunction and apoptosis, for which the mechanisms regulating loss of VSMCs within the aortic wall remain poorly defined. Using single-cell RNA-Seq of human AAA tissues, we identified increased activation of the endoplasmic reticulum stress response pathway, PERK/eIF2α/ATF4, in aortic VSMCs resulting in upregulation of an apoptotic cellular response.
View Article and Find Full Text PDFTRAF6 promotes abdominal aortic aneurysm development by activating macrophage pyroptosis via the NLRP3/Caspase1/GSDMD pathway.
FASEB J
January 2025
Department of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Abdominal aortic aneurysm represents a critical pathology of the aorta that currently lacks effective pharmacological interventions. TNF receptor-associated factor 6 (TRAF6) has been established to be involved in cardiovascular diseases such as atherosclerosis, hypertension, and heart failure. However, its role in abdominal aortic aneurysm (AAA) remains unclear.
View Article and Find Full Text PDFCellular Senescence Genes as Cutting-Edge Signatures for Abdominal Aortic Aneurysm Diagnosis: Potential for Innovative Therapeutic Interventions.
J Cell Mol Med
January 2025
State Key Laboratory of Frigid Zone Cardiovascular Diseases, Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, China.
Abdominal aortic aneurysm (AAA) is the most prevalent dilated arterial aneurysm that poses a significant threat to older adults, but the molecular mechanisms linking senescence to AAA progression remain poorly understood. This study aims to identify cellular senescence-related genes (SRGs) implicated in AAA development and assess their potential as therapeutic targets. Four hundred and twenty-nine differentially expressed genes (DEGs) were identified from the GSE57691 training set, and 867 SRGs were obtained.
View Article and Find Full Text PDFIncomplete remyelination via therapeutically enhanced oligodendrogenesis is sufficient to recover visual cortical function.
Nat Commun
January 2025
Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, CO, USA.
Myelin loss induces neural dysfunction and contributes to the pathophysiology of neurodegenerative diseases, injury conditions, and aging. Because remyelination is often incomplete, better understanding endogenous remyelination and developing remyelination therapies that restore neural function are clinical imperatives. Here, we use in vivo two-photon microscopy and electrophysiology to study the dynamics of endogenous and therapeutic-induced cortical remyelination and functional recovery after cuprizone-mediated demyelination in mice.
View Article and Find Full Text PDFAutophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity.
Nat Metab
January 2025
CECAD Excellence Center, University of Cologne, Cologne, Germany.
Dysfunctions in autophagy, a cellular mechanism for breaking down components within lysosomes, often lead to neurodegeneration. The specific mechanisms underlying neuronal vulnerability due to autophagy dysfunction remain elusive. Here we show that autophagy contributes to cerebellar Purkinje cell (PC) survival by safeguarding their glycolytic activity.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!