The serine protease plasmin plays detrimental roles in epithelial sodium channel activation and podocyte injury in Dahl salt-sensitive rats
The serine protease plasmin plays detrimental roles in epithelial sodium channel activation and podocyte injury in Dahl salt-sensitive rats
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DOI：
10.1038/s41440-022-01064-2
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发表时间：
2022-10-15
影响因子：
5.4
通讯作者：
Mukoyama, Masashi
中科院分区：
文献类型：
--
作者：
Deng, Qinyuan;Kakizoe, Yutaka;Mukoyama, Masashi
盐敏感性高血压与不良临床结局相关。肾脏中的上皮钠通道（ENaC）在钠重吸收和血压调节中起关键作用，其中其γ亚基被细胞外丝氨酸蛋白酶激活。在蛋白尿性肾病中，据报道通过受损肾小球过滤的纤溶酶激活远端肾单位中的γ ENaC并引起足细胞损伤。我们以前报道过，Dahl盐敏感（DS）大鼠喂食高盐（HS）饮食后出现高血压和蛋白尿沿着γ ENaC激活，合成丝氨酸蛋白酶抑制剂甲磺酸卡莫司他可减轻这些变化。然而，纤溶酶在DS大鼠中的作用仍不清楚。在这项研究中，我们评估纤溶酶与高血压的关系，以及足细胞损伤和纤溶酶抑制剂的影响，在DS大鼠。5周龄DS大鼠分为正常盐饮食、HS饮食和HS+纤溶酶抑制剂（氨甲环酸[TA]或合成纤溶酶抑制剂YO-2）组。在5周内测量血压和收集24小时尿液后，处死大鼠进行生化分析。HS组表现出严重的高血压和蛋白尿，以及尿中纤溶酶和肾脏中γ ENaC的活化，YO-2而不是TA显著减弱了这种活化。YO-2通过抑制细胞凋亡和炎性/促纤维化细胞因子，抑制纤溶酶（原）与足细胞的粘附，减轻足细胞损伤。YO-2还抑制蛋白酶激活受体1和磷酸化ERK 1/2的上调。这些结果表明纤溶酶在盐敏感性高血压和相关足细胞损伤的发展中起重要作用，表明纤溶酶抑制剂作为一种潜在的治疗策略。
Salt-sensitive hypertension is associated with poor clinical outcomes. The epithelial sodium channel (ENaC) in the kidney plays pivotal roles in sodium reabsorption and blood pressure regulation, in which its gamma subunit is activated by extracellular serine proteases. In proteinuric nephropathies, plasmin filtered through injured glomeruli reportedly activates gamma ENaC in the distal nephron and causes podocyte injury. We previously reported that Dahl salt-sensitive (DS) rats fed a high-salt (HS) diet developed hypertension and proteinuria along with gamma ENaC activation and that a synthetic serine protease inhibitor, camostat mesilate, mitigated these changes. However, the role of plasmin in DS rats remained unclear. In this study, we evaluated the relationship between plasmin and hypertension as well as podocyte injury and the effects of plasmin inhibitors in DS rats. Five-week-old DS rats were divided into normal-salt diet, HS diet, and HS+plasmin inhibitor (either tranexamic acid [TA] or synthetic plasmin inhibitor YO-2) groups. After blood pressure measurement and 24 h urine collection over 5 weeks, rats were sacrificed for biochemical analyses. The HS group displayed severe hypertension and proteinuria together with activation of plasmin in urine and gamma ENaC in the kidney, which was significantly attenuated by YO-2 but not TA. YO-2 inhibited the attachment of plasmin(ogen) to podocytes and alleviated podocyte injury by inhibiting apoptosis and inflammatory/profibrotic cytokines. YO-2 also suppressed upregulation of protease-activated receptor-1 and phosphorylated ERK1/2. These results indicate an important role of plasmin in the development of salt-sensitive hypertension and related podocyte injury, suggesting plasmin inhibition as a potential therapeutic strategy.