Medipally Ajay, Xiao Min, Biederman Laura, Dasgupta Alana, Satoskar Anjali A, Parikh Samir, Ivanov Iouri, Mikhalina Galina, Brodsky Sergey V
Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States.
Department of Pathology, Nationwide Children's Hospital, Columbus, OH, United States.
Front Nephrol. 2024 Jun 28;4:1406655. doi: 10.3389/fneph.2024.1406655. eCollection 2024.
Anticoagulant related nephropathy (ARN) is the result of glomerular hemorrhage in patients on systemic anticoagulation therapy or underlying coagulopathy. Red blood cells (RBC) that passed through the glomerular filtration barrier form RBC casts in the tubules, increase oxidative stress and result in acute tubular necrosis (ATN). The mechanisms of ARN still not completely discovered. Plasminogen activator inhibitor-1 (PAI-1) plays a significant role in the maintenance of coagulation homeostasis. We developed an animal model to study ARN in 5/6 nephrectomy (5/6NE) rats. The aim of this study was to elucidate the role of PAI-1 in the ARN pathogenesis. 5/6NE rats were treated per os with warfarin (0.75 mg/kg/day) or dabigatran (150 mg/kg/day) alone or in combination with PAI-1 antagonist TM5441 (2.5, 5.0 and 10 mg/kg/day). TM5441 in a dose dependent manner ameliorated anticoagulant-induced increase in serum creatinine in 5/6NE rats. Anticoagulant-associated increase in hematuria was no affected by TM5441. The levels of reactive oxygen species (ROS) in the kidneys were in a dose-dependent manner decreased in 5/6NE rats treated with an anticoagulant and TM5441. Our data demonstrates that PAI-1 may reduce ARN by decreasing ROS in the kidneys. Glomerular hemorrhage is not affected by anti-PAI-1 treatment. These findings indicate that while symptoms of ARN can be reduced by PAI-1 inhibition, the main pathogenesis of ARN - glomerular hemorrhage - cannot be prevented.
抗凝相关肾病（ARN）是全身抗凝治疗或潜在凝血病患者肾小球出血的结果。穿过肾小球滤过屏障的红细胞（RBC）在肾小管中形成红细胞管型，增加氧化应激并导致急性肾小管坏死（ATN）。ARN的发病机制尚未完全明确。纤溶酶原激活物抑制剂-1（PAI-1）在维持凝血稳态中起重要作用。我们建立了一种动物模型来研究5/6肾切除（5/6NE）大鼠的ARN。本研究的目的是阐明PAI-1在ARN发病机制中的作用。5/6NE大鼠经口给予华法林（0.75 mg/kg/天）或达比加群（150 mg/kg/天），单独使用或与PAI-1拮抗剂TM5441（2.5、5.0和10 mg/kg/天）联合使用。TM5441以剂量依赖的方式改善了抗凝剂诱导的5/6NE大鼠血清肌酐升高。TM5441对抗凝剂相关的血尿增加没有影响。在接受抗凝剂和TM5441治疗的5/6NE大鼠中，肾脏中的活性氧（ROS）水平呈剂量依赖性降低。我们的数据表明，PAI-1可能通过降低肾脏中的ROS来减轻ARN。抗PAI-1治疗不影响肾小球出血。这些发现表明，虽然抑制PAI-1可以减轻ARN的症状，但ARN的主要发病机制——肾小球出血——无法预防。
