Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, J. B. Winsløws Vej 21, 3., 5000, Odense, Denmark.
Pflugers Arch. 2017 Nov;469(11):1415-1423. doi: 10.1007/s00424-017-2014-y. Epub 2017 Jun 27.
The plasminogen system is important for fibrinolysis in addition to tissue remodeling and inflammation with significance for kidney disease. The system consists of the circulating zymogen plasminogen (Plg) and the tissue- and urokinase-type plasminogen activators, tPA and uPA, expressed in the glomeruli, endothelium and tubular epithelium, respectively, and the inhibitors α-antiplasmin and plasminogen activator inhibitor-type1, PAI-1. Plasminogen is activated by surface receptors, some with renal expression: urokinase-type plasminogen activator receptor (uPAR), plasminogen receptor KT (Plg-R), and tPA, most evident in the endothelium. Plasmin may exert effects through protease-activated receptors, PARs, expressed in the kidney. Deletion of plasminogen system component genes confers no major developmental or renal phenotypes in normal mice. In glomerular injury and renal interstitial fibrosis, deletion of various components, notably Plg, uPA, PAI, and uPAR is associated with protection suggesting a disease promoting effect of plasmin, in some cases exerted through PAR1 receptor activation. Plasminogen and uPA are aberrantly filtrated across the glomerular barrier in proteinuria, and plasminogen is activated in the tubular fluid. In the tubular fluid, plasmin may activate proteolytically the epithelial sodium channel (ENaC) and inhibit the apical calcium transporter transient receptor potential cation channel subfamily V member 5 (TRPV5), which could explain impaired sodium excretion and enhanced calcium excretion in proteinuria. Amiloride, a potassium-sparing diuretic, inhibits urokinase and plasmin activation in the tubular fluid and uPAR expression in vitro, which highlights new indications for an old drug. Protease inhibitors lowered blood pressure and antagonized fibrosis in salt-sensitive Dahl rats. Current knowledge indicates that the plasminogen system aggravates renal disease by direct and indirect hypertensive effects and is a promising target to antagonize disease progression.
纤溶系统除了在组织重塑和炎症中具有重要作用外，对肾脏疾病也具有重要意义。该系统包括循环酶原纤溶酶原（Plg）和组织型及尿激酶型纤溶酶原激活物，tPA 和 uPA，分别在肾小球、内皮细胞和肾小管上皮细胞中表达，以及抑制剂α2-抗纤溶酶和纤溶酶原激活物抑制剂-1，PAI-1。纤溶酶原通过表面受体激活，其中一些在肾脏中表达：尿激酶型纤溶酶原激活物受体（uPAR）、纤溶酶原受体 KT（Plg-R）和 tPA，在内皮细胞中最为明显。纤溶酶可能通过蛋白酶激活受体（PARs）发挥作用，PARs 在肾脏中表达。在正常小鼠中，纤溶系统成分基因缺失不会导致主要的发育或肾脏表型。在肾小球损伤和肾间质纤维化中，各种成分，特别是 Plg、uPA、PAI 和 uPAR 的缺失与保护有关，这表明纤溶酶具有促进疾病的作用，在某些情况下，通过 PAR1 受体的激活发挥作用。纤溶酶原和 uPA 在蛋白尿中异常滤过肾小球屏障，在管状液中被激活。在管状液中，纤溶酶可能通过蛋白水解激活上皮钠通道（ENaC）并抑制顶端钙转运体瞬时受体电位阳离子通道亚家族 V 成员 5（TRPV5），这可以解释蛋白尿中钠排泄受损和钙排泄增加的原因。阿米洛利，一种保钾利尿剂，可抑制管状液中的尿激酶和纤溶酶激活以及 uPAR 的表达，这突出了一种旧药物的新适应症。蛋白酶抑制剂可降低血压并拮抗盐敏感型 Dahl 大鼠的纤维化。目前的知识表明，纤溶系统通过直接和间接的高血压作用加重肾脏疾病，是拮抗疾病进展的有希望的靶点。
