Plasminogen activator inhibitor-1 deficiency retards diabetic nephropathy
Plasminogen activator inhibitor-1 deficiency retards diabetic nephropathy
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DOI：
10.1111/j.1523-1755.2005.00207.x
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发表时间：
2005-04-01
影响因子：
19.6
通讯作者：
Hsueh, WA
中科院分区：
文献类型：
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作者：
Nicholas, SB;Aguiniga, E;Hsueh, WA
背景。纤溶酶原激活物抑制剂-1 （PAI-1）在糖尿病肾病的人和动物肾脏中升高，并与细胞外基质（ECM）积累有关。PAI-1可能通过阻止纤溶酶和基质金属蛋白酶（MMP）的激活而促进ECM的形成。然而，PAI-1在糖尿病肾病发病中的作用及其机制尚不清楚。我们研究了链脲佐菌素（STZ）对野生型（PAI-1(+/+)）小鼠和PAI-1阴性小鼠（PAI-1(-/-)）诱导的糖尿病的影响。糖尿病1个月后，将动物置于代谢笼中，24小时收集尿液。从肾皮质提取总RNA进行逆转录聚合酶链反应（RT-PCR）和Northern blot分析，并对皮质蛋白进行Western blot检测。在Sprague-Dawley大鼠身上培养原代系膜细胞，并将其用于信号转导研究。糖尿病PAI-1（+/+）小鼠的尿白蛋白排泄量（UAE）增加了3倍，但在PAI-1（-/-）小鼠中保持不变。糖尿病PAI-1（-/-）小鼠与PAI-1（+/+）小鼠相比，转化生长因子- β (tgf - β)和纤维连接蛋白的信息和蛋白水平较低，表明尽管患有糖尿病，但PAI-1缺乏也会损害tgf - β的表达。事实上，重组PAI-1在培养的系膜细胞中通过丝裂原活化蛋白激酶（MAPK）信号转导直接刺激tgf - β信息和蛋白。尿激酶纤溶酶原激活剂（uPA）以剂量依赖性的方式抑制PAI-1的作用。uPA受体抗体（uPAR）对pai -1诱导的tgf - β功能的抑制作用提示uPAR介导了pai -1的细胞效应。PAI-1可以通过与uPAR结合并激活细胞外调节信号激酶(ERK)/MAPK通路来调节tgf - β的表达。因此，PAI-1通过调节tgf - β和肾ECM的产生参与糖尿病肾病，可能是糖尿病肾病的治疗靶点。
Background. Plasminogen activator inhibitor-1 (PAI-1) is increased in kidneys of humans and animals with diabetic nephropathy and is associated with extracellular matrix (ECM) accumulation. PAI-1 may promote ECM buildup by preventing plasmin and matrix metalloproteinase (MMP) activation. However, the importance and mechanism of PAI-1 action in the pathogenesis of diabetic nephropathy is unknown.Methods. We investigated the effect of streptozotocin (STZ)-induced diabetes in wild-type (PAI-1(+/+)) mice and mice null for PAI-1 (PAI-1(-/-)). After 1 month of diabetes, animals were placed in metabolic cages for 24-hour urine collection. Total RNA was isolated from kidney cortex for reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot analysis, and Western blots were quantitated from cortical protein. Primary mesangial cells were grown from Sprague-Dawley rats and used in signal transduction studies.Results. Urinary albumin excretion (UAE) in diabetic PAI-1(+/+) mice increased > threefold, but remained unchanged in PAI-1(-/-) mice. Transforming growth factor-beta (TGF-beta) and fibronectin message and protein levels were lower in diabetic PAI-1(-/-) vs. PAI-1(+/+) mice, suggesting that PAI-1 deficiency impaired TGF-beta expression despite diabetes. Indeed, recombinant PAI-1 directly stimulated TGF-beta message and protein via mitogen-activated protein kinase (MAPK) signal transduction in cultured mesangial cells. Urokinase plasminogen activator (uPA) inhibited this PAI-1 action in a dose-dependent manner. The inhibitory effect of antibody to uPA receptor (uPAR) on PAI-1-induced TGF-beta function suggested that uPAR mediated the cellular effect of PAI-1.Conclusion. PAI-1 can regulate TGF-beta expression by binding to uPAR and activating the extracellular-regulated signal kinase (ERK)/MAPK pathway. Therefore, PAI-1 contributes to diabetic nephropathy by regulating TGF-beta and renal ECM production and may be a therapeutic target in diabetic nephropathy.