Kagami S, Kondo S, Löster K, Reutter W, Kuhara T, Yasutomo K, Kuroda Y
Department of Pediatrics, School of Medicine, University of Tokushima, Japan.
J Am Soc Nephrol. 1999 Apr;10(4):779-89. doi: 10.1681/ASN.V104779.
Pathologic remodeling of mesangial matrix after glomerular injury is the central biologic feature of glomerular scarring (sclerosis). Transforming growth factor-beta (TGF-beta) and platelet-derived growth factor (PDGF)-BB have been implicated in the development of glomerular scarring in rat and human glomerulonephritis. To clarify molecular and cellular mechanisms involved in abnormal mesangial remodeling, this study focused on the role of alpha1beta1 integrin, a collagen/laminin receptor, in rat mesangial cells, using collagen gel contraction as an experimental model of in vivo collagen matrix remodeling and scar formation. In addition, the influence of TGF-beta and PDGF-BB on mesangial cell (MC)-mediated collagen gel contraction in association with the alpha1beta1 integrin expression was evaluated. Integrin function blocking studies using anti-alpha1, beta1 subunit antibodies indicated that MC-alpha1beta1 integrin is essentially required not only for collagen-dependent adhesion/migration, but also for gel contraction. Protein synthesis and mRNA analysis experiments demonstrated that TGF-beta, but not PDGF-BB, increases the expression of alpha1beta1 integrin in mesangial cells cultured on plastic surface and in collagen gels. The upregulation of alpha1beta1 integrin expression by TGF-beta correlated with increases in gel contraction and collagen-dependent adhesion but not migration of mesangial cells. On the other hand, PDGF-BB enhanced MC-mediated gel contraction and migration without affecting cell adhesion to collagen I. Growth factor-induced collagen-dependent adhesion, migration, and gel contraction were significantly attenuated by incubation with anti-alpha1, beta1 subunit antibodies. Thus, these data indicate that alpha1beta1 integrin-mediated collagen matrix remodeling can be modulated by TGF-beta and PDGF-BB via different mechanisms. Alpha1 integrin-mediated mesangial matrix remodeling induced by TGF-beta or PDGF-BB may be a pathogenic mechanism leading to glomerular scarring.
肾小球损伤后系膜基质的病理性重塑是肾小球瘢痕形成（硬化）的核心生物学特征。转化生长因子-β（TGF-β）和血小板衍生生长因子（PDGF）-BB已被认为与大鼠和人类肾小球肾炎中肾小球瘢痕的形成有关。为了阐明系膜异常重塑所涉及的分子和细胞机制，本研究以α1β1整合素（一种胶原/层粘连蛋白受体）在大鼠系膜细胞中的作用为重点，采用胶原凝胶收缩作为体内胶原基质重塑和瘢痕形成的实验模型。此外，还评估了TGF-β和PDGF-BB对系膜细胞（MC）介导的胶原凝胶收缩以及α1β1整合素表达的影响。使用抗α1、β1亚基抗体进行的整合素功能阻断研究表明，MC-α1β1整合素不仅对于胶原依赖性黏附/迁移是必需的，而且对于凝胶收缩也是必需的。蛋白质合成和mRNA分析实验表明，TGF-β而非PDGF-BB可增加在塑料表面和胶原凝胶中培养的系膜细胞中α1β1整合素的表达。TGF-β引起的α1β1整合素表达上调与凝胶收缩增加以及系膜细胞的胶原依赖性黏附增加相关，但与迁移无关。另一方面，PDGF-BB增强了MC介导的凝胶收缩和迁移，但不影响细胞与I型胶原的黏附。与抗α1、β1亚基抗体孵育后，生长因子诱导的胶原依赖性黏附、迁移和凝胶收缩均显著减弱。因此，这些数据表明，α1β1整合素介导的胶原基质重塑可通过不同机制被TGF-β和PDGF-BB调节。TGF-β或PDGF-BB诱导的α1整合素介导的系膜基质重塑可能是导致肾小球瘢痕形成的致病机制。
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