ANTAGONISTS OF TRANSFORMING GROWTH-FACTOR-BETA - A NOVEL-APPROACH TO TREATMENT OF GLOMERULONEPHRITIS AND PREVENTION OF GLOMERULOSCLEROSIS
ANTAGONISTS OF TRANSFORMING GROWTH-FACTOR-BETA - A NOVEL-APPROACH TO TREATMENT OF GLOMERULONEPHRITIS AND PREVENTION OF GLOMERULOSCLEROSIS
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DOI：
10.1038/ki.1992.83
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发表时间：
1992-03-01
影响因子：
19.6
通讯作者：
KAGAMI, S
中科院分区：
文献类型：
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作者：
BORDER, WA;NOBLE, NA;KAGAMI, S
转化生长因子-α（TGF-β）是多肽调节因子的原型[1]。TGF-β以三种同种型TGF-β 1、TGF-β 2和TGF-β 3存在于哺乳动物中，并作用于几乎每种哺乳动物细胞类型，调节一系列细胞功能。TGF-β是多功能的，因为根据细胞的状态或背景，TGF-β可以刺激或抑制相同的过程[2]。TGF-β最重要的特性之一是其对细胞外基质的广泛影响。体内的大多数细胞，包括肾小球系膜细胞，被称为细胞外基质的相互作用的糖蛋白、胶原和蛋白聚糖的复杂超结构包围[3]。肾小球基底膜代表肾小球中特化细胞外基质的第二种形式。这两种肾小球基质在确定渗透性和滤过的生物物理特性方面都很重要。所有细胞都具有特异性基质表面受体，通过该受体它们粘附到基质上[41]。细胞附着于基质允许细胞生长、分裂、分化、分泌产物、移动和形成特化组织。TGF-β 3通过其已知的作用影响所有这些细胞功能：1）刺激细胞外基质分子的产生; 2）抑制降解基质的酶; 3）增加基质受体的表达和粘附表型[1]。总的来说，TGF-β 3起到增强细胞外基质积累的作用，这在诸如伤口修复的过程中是非常有益的，但当其在肾小球肾炎或糖尿病性肾病的肾小球中发生时是有害的[51]。我们实验室的最新证据表明，TGF-β 3作为伤口修复的主要调节因子的作用与TGF-β参与实验性肾小球肾炎之间存在惊人的相似性（图1）。TGF-β 3在皮肤创伤修复中的作用的结果是形成疤痕。在肾小球中，同样的过程可以导致硬化。因此，肾小球硬化症可以被视为TGF-β 3和伤口修复的”阴暗面”。这一逻辑暗示了治疗的双重作用。在某些情况下，额外的TGF-β 3是有益的（伤口修复），而在其他情况下，需要TGF-β 3的拮抗作用（肾小球硬化）[5]。最重要的是公认的TGF-β启动然后终止修复过程的能力。未能终止TGF-β在肾小球中的作用将为进行性肾小球硬化奠定基础。TGF-β 1参与实验性肾小球肾炎的证据如下。
Transforming growth factor-a (TGF-/3) is the prototype of a polypeptide regulatory factor [1]. TGF-13 exists in mammals in three isoforms, TGF-j31, 2 and 3 and acts on virtually every mammalian cell type regulating an array of cellular functions. TGF-/3 is multifunctional in that depending on the state or context of the cell, TGF-/3 can either stimulate or inhibit the same process [2]. One of the most important properties of TGF-/3 is its widespread effects on extracellular matrix. Most cells in the body, including glomerular mesangial cells, are surrounded by a complex superstructure of interacting glycoproteins, collagens and proteoglycans called extracellular ma-trix [3]. The glomerular basement membrane represents a second form of specialized extracellular matrix in the glomerulus. Both glomerular matrices are important in determining the biophysical properties of permeability and filtration. All cells possess specific matrix surface receptors through which they adhere to the matrix [41. Cellular attachment to the matrix allows cells to grow, divide, differentiate, secrete products, move and form specialized tissues. TGF-f3 influences all of these cellular functions through its known actions to: 1) stimulate the production of extracellular matrix molecules; 2) inhibit enzymes that degrade matrix; and 3) increase the expression and adhesion phenotype of matrix receptors [1]. Collectively, TGF-f3 acts to enhance accumulation of extracellular matrix which is highly beneficial in a process such as wound repair, but deleterious when it occurs in the glomerulus in glomerulonephritis or diabetic nephropathy [51. Recent evidence from our laboratory suggests that there are striking similarities between the role of TGF-f3 as a master regulator of wound repair, and the involvement of TGF-p in experimental glomerulonephritis (Fig. 1). The result of the action of TGF-f3 in wound repair in the skin is the formation of a scar. In the glomerulus, the same process can lead to sclerosis. Thus glomeruloscierosis can be viewed as the" dark side" of TGF-j3 and wound repair. This logic suggests a dual role for therapy. In some cases additional TGF-f3 is beneficial (wound repair) and in others, antagonism of TGF-/3 (glomeru-losclerosis) is required [5].© 1992 by the International Society of NephrologyThe known actions of TGF-/3 in wound repair are depicted in Figure 2. Most important is the recognized ability of TGF-p to initiate and then terminate the repair process. Failure to terminate the action of TGF-/3 in the glomerulus would set the stage for progressive glomerulosclerosis. Evidence for the involvement of TGF-/3 in experimental glomerulonephritis is as fol-lows.