Role of protease-activated receptor-1 (PAR-1) in the glomerular filtration barrier integrity.
Role of protease-activated receptor-1 (PAR-1) in the glomerular filtration barrier integrity.
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DOI：
10.14814/phy2.15343
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发表时间：
2022-08
影响因子：
2.5
通讯作者：
中科院分区：
文献类型：
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蛋白酶激活受体（PAR）在凝血系统细胞功能的调节中发挥着重要作用，它们被凝血酶激活。 PAR-1 在肾脏的内皮细胞和足细胞中表达。 PAR1 在维持肾小球滤过屏障中的作用尚不清楚。抗凝相关性肾病（ARN）是一种以肾小球血尿和红细胞管型为特征的肾脏疾病。我们验证了大鼠 5/6 肾切除术 (5/6NE) 作为 ARN 模型，并证明直接凝血酶抑制剂（达比加群）可诱导 ARN。本研究的目的是探讨 PAR-1 在 ARN 发病机制中的作用。 5/6NE 大鼠接受达比加群（150 mg/kg/天）、PAR-1 抑制剂 SCH79797（1 和 3 mg/kg/天）和 PAR-1 激动剂 TFLLR-NH2（0.25 和 0.50 µmol/kg/天）治疗 7 天。每天评估血清肌酐和血尿。在研究结束时评估肾脏形态。在使用达比加群或与 PAR-1 调节剂联合治疗的 5/6NE 大鼠中，血清肌酐升高、肾小球血尿、肾小管红细胞管型和急性肾小管上皮细胞损伤。有趣的是，两种 PAR-1 调节剂以剂量依赖性方式对血清肌酐水平和血尿具有与达比加群相似的影响。达比加群引起的收缩压升高不受 PAR-1 调节剂的影响。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 的激活或阻断会导致肾小球血尿和随后的急性肾小管上皮细胞损伤。使用 PAR-1 调节剂（含或不含直接凝血酶抑制剂达比加群）治疗的动物的红细胞管型。
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. Red blood cell tubular casts in animals treated with PAR‐1 modulators with and without direct thrombin inhibitor dabigatran.
影响因子：
2.5
作者：
Medipally AK;Xiao M;Rovin BH;Satoskar AA;Ivanov I;Qaisar S;Brodsky SV
通讯作者：
Brodsky SV