Departments of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Departments of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Physiol Rep. 2022 Aug;10(15):e15343. doi: 10.14814/phy2.15343.
Protease-activated receptors (PAR) play an important role in the regulation of cellular function by the coagulation system, and they are activated by thrombin. PAR-1 is expressed in both endothelial cells and podocytes in the kidney. The role of PAR1 in the maintenance of the glomerular filtration barrier is not clear. Anticoagulant-related nephropathy (ARN) is a kidney disease with glomerular hematuria and red blood cell tubular casts. We validated 5/6 nephrectomy (5/6NE) in rats as a model of ARN and had demonstrated that direct thrombin inhibitor (dabigatran) induces ARN. The aim of this study was to investigate the role of PAR-1 in the ARN pathogenesis. 5/6NE rats were treated with dabigatran (150 mg/kg/day), PAR-1 inhibitor SCH79797 (1 and 3 mg/kg/day) and PAR-1 agonist TFLLR-NH2 (0.25 and 0.50 µmol/kg/day) for 7 days. Serum creatinine and hematuria were assessed daily. Kidney morphology was evaluated at the end of the study. In 5/6NE rats treated with either dabigatran or combination with a PAR-1 modulator, there was an elevation in serum creatinine, glomerular hematuria, red blood casts in the tubules, and acute tubular epithelial cell injury. Interestingly, both PAR-1 modulators in a dose-depended manner had similar effects on the serum creatinine levels and hematuria as those of dabigatran. Dabigatran-induced increase in the systolic blood pressure was not affected by PAR-1 modulators. In conclusion, the normal function of PAR-1 is crucial to maintain the glomerular filtration barrier integrity. Either activation or blockage of PAR-1 leads to glomerular hematuria and subsequent acute tubular epithelial cell injury.
蛋白酶激活受体（PAR）在凝血系统调节细胞功能方面发挥着重要作用，并且可被凝血酶激活。PAR-1 在肾脏的内皮细胞和足细胞中均有表达。PAR1 在维持肾小球滤过屏障中的作用尚不清楚。抗凝相关肾病（ARN）是一种以肾小球性血尿和红细胞管状铸型为特征的肾脏疾病。我们验证了大鼠的 5/6 肾切除术（5/6NE）作为 ARN 模型，并证明了直接凝血酶抑制剂（达比加群）可诱导 ARN。本研究旨在探讨 PAR-1 在 ARN 发病机制中的作用。5/6NE 大鼠给予达比加群（150mg/kg/天）、PAR-1 抑制剂 SCH79797（1 和 3mg/kg/天）和 PAR-1 激动剂 TFLLR-NH2（0.25 和 0.50µmol/kg/天）治疗 7 天。每天评估血清肌酐和血尿。研究结束时评估肾脏形态。在接受达比加群或与 PAR-1 调节剂联合治疗的 5/6NE 大鼠中，血清肌酐、肾小球性血尿、肾小管内红细胞铸型和急性肾小管上皮细胞损伤均升高。有趣的是，两种 PAR-1 调节剂均以剂量依赖性方式对血清肌酐水平和血尿产生与达比加群相似的作用。PAR-1 调节剂对达比加群诱导的收缩压升高没有影响。总之，PAR-1 的正常功能对于维持肾小球滤过屏障的完整性至关重要。PAR-1 的激活或阻断均可导致肾小球性血尿和随后的急性肾小管上皮细胞损伤。
