CYTOKINES IN KIDNEY-DISEASE - THE ROLE OF TRANSFORMING GROWTH-FACTOR-BETA
CYTOKINES IN KIDNEY-DISEASE - THE ROLE OF TRANSFORMING GROWTH-FACTOR-BETA
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DOI：
10.1016/s0272-6386(12)70175-0
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发表时间：
1993-07-01
影响因子：
13.2
通讯作者：
NOBLE, NA
中科院分区：
文献类型：
--
作者：
BORDER, WA;NOBLE, NA
转化生长因子-β (TGF-β) 等细胞因子是调节胚胎发生、发育、炎症、组织修复和癌变的肽因子。越来越多的证据表明，细胞因子作用失调可能是严重自身免疫、退行性和纤维化疾病发病机制的基础。对急性系膜增生性肾小球肾炎模型的研究表明，TGF-β的过量产生是肾小球细胞外基质病理性积聚的原因。转化生长因子-β 可增加肾小球肾炎大鼠的基质产生、抑制基质降解并调节基质受体。它还可能在肾小球基质形成中发挥作用，肾小球基质形成是糖尿病肾病的核心特征。在糖尿病大鼠的肾小球中发现 TGF-β mRNA 和 TGF-β 蛋白表达升高，同时蛋白聚糖和已知由 TGF-β 诱导的其他基质成分水平升高。对人类糖尿病肾小球的研究也显示 TGF-ft 蛋白水平显着升高。正常肾脏和非进行性肾脏疾病的肾小球呈阴性。 TGF-β 引起旺盛基质形成的惊人能力可能是由于 TGF-β 可以诱导损伤部位的常驻细胞自行产生。因此，TGF-β 造成伤害的可能性可能是由于这种自诱导机制，TGF-β 的表达可能会变得慢性，从而形成恶性循环。随着 TGF-ft 在慢性纤维化疾病中的作用得到更好的了解，TGF-β 抑制剂很可能成为未来治疗这些疾病的重要药物。迄今为止，中和抗体已成功阻断肾脏、皮肤和中枢神经系统中的 TGF-β 活性。在每种情况下，抑制TGFβ都显着减少了过量细胞外基质的积累，但不干扰正常组织修复。最近，人们发现蛋白聚糖核心蛋白聚糖可能是TGF-β的天然调节因子。将重组人核心蛋白聚糖注射到肾小球肾炎大鼠体内，可显着阻断肾小球肾小球中细胞外基质的积聚，并抑制蛋白尿的发生。由于核心蛋白聚糖是一种天然的人类化合物，可以作为重组分子生产，因此与抗体相比，它可能不具有免疫原性。核心蛋白聚糖为治疗与 TGF-β 过度产生相关的慢性疾病带来了希望。
Cytokines such as transforming growth factor-β (TGF-β) are peptide factors that regulate embryogenesis, development, inflammation, tissue repair, and carcinogenesis. Growing evidence indicates that dysregulation of cytokine actions may underlie the pathogenesis of serious autoimmune, degenerative, and fibrotic diseases. Studies in a model of acute mesangial proliferative glomerulonephritis show that overproduction of TGF-β is the cause of pathologic accumulation of extracellular matrix in the nephritic glomeruli. Transforming growth factor-β acts to increase matrix production, inhibit matrix degradation, and modulate matrix receptors in the glomerulonephritic rats. It may also play a role in the glomerular matrix build-up that is a central feature of diabetic nephropathy. Elevated expression of TGF-β mRNA and TGF-β protein were found in the glomeruli of diabetic rats along with increased levels of proteoglycans and other matrix components that are known to be induced by TGF-β. The study of human diabetic glomeruli has also shown markedly elevated levels of TGF-ft protein. Glomeruli from normal kidneys and nonprogressive kidney disorders were negative. The striking ability of TGF-β to cause exuberant matrix formation may be due to the fact that TGF-β can induce its own production by resident cells at a site of injury. Thus, the potential for TGF-β to do harm may be due to this autoinduction mechanism whereby TGF-β expression can become chronic, creating a vicious circle. As the role that TGF-ft plays in chronic fibrotic diseases becomes better understood, it is likely that TGF-β inhibitors will become important future drugs for treating these conditions. To date, TGF-β activity has been successfully blocked in the kidney, in the skin, and in the central nervous system by neutralizing antibodies. In each case, inhibiting TGFβ significantly decreased the accumulation of excessive extracellular matrix but did not interfere with normal tissue repair. Recently, it has been discovered that the proteoglycan decorin may be a natural regulator of TGF-β. Injection of recombinant human decorin into glomerulonephritic rats significantly blocked extracellular matrix build-up in the nephritic glomeruli and suppressed the development of proteinuria. Since decorin is a natural human compound that can be produced as a recombinant molecule, it is likely not to be immunogenic compared with antibodies. Decorin offers hope as a treatment for chronic diseases associated with the overproduction of TGF-β.