Zhe Wang

Platelet dysfunction drives bleeding complications in patients with advanced chronic kidney disease (CKD), worsening clinical outcomes. However, the underlying mechanisms remain unclear, limiting treatment options. In this study, we identified the expression of urea transporter B (SLC14A1/UT-B) in human and mouse platelets. By analyzing a clinical cohort of patients with CKD, we demonstrated that single-nucleotide polymorphisms in SLC14A1 were associated with bleeding events in CKD. Using a 5/6 nephrectomy (5/6 Nx) mouse model and blood samples from patients with advanced CKD, we found that SLC14A1/UT-B–mediated urea influx underlies platelet dysfunction in advanced CKD given that both genetic knockout of Slc14a1 or pharmacological inhibition of UT-B reversed mouse and human platelet dysfunction induced by urea or advanced CKD plasma. SLC14A1/UT-B–mediated urea influx induced protein carbamylation, which drove platelet dysfunction. By characterizing the carbamylation profiles of proteins in human and mouse platelets, we demonstrated that carbamylation disrupted cytoskeletal rearrangement, degranulation, and inside-out integrin αIIbβ3 signaling transduction during platelet activation, leading to impaired platelet aggregation, secretion, and spreading in advanced CKD. Furthermore, treatment of 5/6 Nx mice with the UT-B inhibitor PU-48 effectively preserved platelet function and improved hemostatic ability. These findings suggest that SLC14A1/UT-B promoted urea uptake in platelets and mediated bleeding in advanced CKD, highlighting its potential as a therapeutic target for managing bleeding complications in patients with advanced CKD.

Endothelial cells (ECs) line the inner surface of blood vessels and play a substantial role in vascular biology. Endothelial dysfunction (ED) is strongly correlated with the initiation and progression of many vascular diseases. Regulated cell death, such as ferroptosis, is one of the multiple mechanisms that lead to ED. Ferroptosis is an iron-dependent programmed cell death associated with various vascular diseases, such as cardiovascular, cerebrovascular, and pulmonary vascular diseases. This review summarized ferroptosis of ECs in vascular diseases and discussed potential therapeutic strategies for treating ferroptosis of ECs. In addition to lipid peroxidation inhibitors and iron chelators, a growing body of evidence showed that clinical drugs, natural products, and intervention of noncoding RNAs may also inhibit ferroptosis of ECs.

(1) Background: The purpose of this study was to evaluate the effect of gene polymorphisms on prothrombin time (PT) and activated partial thromboplastin time (APTT) in a healthy Chinese population. (2) Methods: A total of 403 healthy volunteers from a series of novel oral anticoagulants (NOACs) bioequivalence trials in China were included. Coagulation tests for PT and APTT were performed in the central lab at Peking University First Hospital. Whole-exome sequencing (WES) and genome-wide association analysis were performed. (3) Results: In the correlation analysis of PT, 105 SNPs from 84 genes reached the genome-wide significance threshold (p < 1 × 10⁻⁵). Zinc Finger Protein 594 (ZNF594) rs184838268 (p = 4.50 × 10⁻¹⁹) was most significantly related to PT, and Actinin Alpha 1 (ACTN1) was found to interact most with other candidate genes. Significant associations with previously reported candidate genes Aurora Kinase B (AURKB), Complement C5(C5), Clock Circadian Regulator (CLOCK), and Histone Deacetylase 9(HDAC9) were detected in our dataset (p < 1 × 10⁻⁵). PiggyBac Transposable Element Derived 2(PGBD2) rs75935520 (p = 4.49 × 10⁻⁶), Bromodomain Adjacent To Zinc Finger Domain 2A(BAZ2A) rs199970765 (p = 5.69 × 10⁻⁶) and Protogenin (PRTG) rs80064850 (p = 8.69 × 10⁻⁶) were significantly correlated with APTT (p < 1 × 10⁻⁵). The heritability values of PT and APTT were 0.83 and 0.64, respectively; (4) Conclusion: The PT and APTT of healthy populations are affected by genetic polymorphisms. ZNF594 and ACTN1 variants could be novel genetic markers of PT, while PRTG polymorphisms might be associated with APTT levels. The findings could be attributed to ethnic differences, and need further investigation.