Department of Clinical Nutrition, Medical University of Gdańsk, Gdańsk 80-211, Poland.
Int J Mol Med. 2013 Mar;31(3):503-10. doi: 10.3892/ijmm.2013.1234. Epub 2013 Jan 10.
Plasminogen activator inhibitor type-1 (PAI-1) inhibits tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA), which convert plasminogen to plasmin, a strong proteolytic enzyme. Thus, PAI-1 is a primary and negative regulator of plasmin-driven proteolysis. In addition to its main role as an inhibitor of fibrinolysis, PAI‑1 has been implicated as a mediator in other processes, including fibrosis, rheumatoid arthritis, atherosclerosis, tumor angiogenesis and bacterial infections. It also significantly modulates cellular adhesion or migration, wound healing, angiogenesis and tumor cell metastasis. However, in the present study, we have reviewed the literature in relation to different kidney diseases where PAI-1 regulates fibrinolysis and acts independently of proteolysis. PAI-1 is normally produced in trace amounts in healthy kidneys but is synthesized in a wide variety of both acute and chronic diseased kidneys. We reviewed the role of PAI-1 in diabetic kidney nephropathy, chronic kidney disease, hemodialysis, peritoneal dialysis and in kidney transplantation. Increased PAI-1 expression results in accumulation of extracellular matrix (ECM) leading to numerous kidney diseases. Predisposition to some diseases is due to the genetic role of PAI-1 in their development. A number of studies demonstrated that the inhibition of PAI-1 activity or therapy with a mutant PAI-1 increases matrix turnover and reduces glomerulosclerosis by competing with endogenous PAI-1. This strongly suggests that PAI-1 is a valid target in the treatment of fibrotic renal disease. However, net proteolytic activity depends on the delicate balance between its negative regulation by PAI-1 and activation by uPA and tPA. Also, plasmin activated by its inhibitors upregulates activity of other enzymes. Thus, assessment of prognosis for the diseased kidney should include a variety of proteolysis regulators and enzymes.
纤溶酶原激活物抑制剂-1（PAI-1）抑制组织型纤溶酶原激活物（tPA）和尿激酶型纤溶酶原激活物（uPA），这两种酶可将纤溶酶原转化为纤溶酶，这是一种强有力的蛋白水解酶。因此，PAI-1 是纤溶酶驱动的蛋白水解的主要负调控因子。除了作为纤维蛋白溶解的主要抑制剂外，PAI-1 还被认为是其他过程的介质，包括纤维化、类风湿性关节炎、动脉粥样硬化、肿瘤血管生成和细菌感染。它还显著调节细胞黏附或迁移、伤口愈合、血管生成和肿瘤细胞转移。然而，在本研究中，我们综述了与 PAI-1 调节纤维蛋白溶解且独立于蛋白水解作用的不同肾脏疾病相关的文献。PAI-1 在健康肾脏中微量产生，但在各种急性和慢性肾脏疾病中广泛合成。我们综述了 PAI-1 在糖尿病肾病、慢性肾脏病、血液透析、腹膜透析和肾移植中的作用。PAI-1 表达增加导致细胞外基质（ECM）的积累，导致多种肾脏疾病。某些疾病的易感性归因于 PAI-1 在其发病机制中的遗传作用。许多研究表明，PAI-1 活性的抑制或用突变型 PAI-1 治疗可通过与内源性 PAI-1 竞争增加基质周转并减少肾小球硬化。这强烈表明 PAI-1 是治疗纤维性肾脏疾病的有效靶点。然而，净蛋白水解活性取决于 PAI-1 的负调节及其与 uPA 和 tPA 的激活之间的微妙平衡。此外，其抑制剂激活的纤溶酶可上调其他酶的活性。因此，对患病肾脏的预后评估应包括多种蛋白水解调节剂和酶。
