Kawaguchi Yasushi, Takagi Kae, Hara Masako, Fukasawa Chikako, Sugiura Tomoko, Nishimagi Emi, Harigai Masayoshi, Kamatani Naoyuki
Tokyo Women's Medical University School of Medicine, Tokyo, Japan.
Arthritis Rheum. 2004 Jan;50(1):216-26. doi: 10.1002/art.11364.
Tissue fibrosis in systemic sclerosis (SSc) is attributed to excessive deposition of extracellular matrix components produced by fibroblasts in skin lesions. Angiotensin II (Ang II), a vasoconstrictive peptide, is reported to have profibrotic activity as a result of induction of the extracellular matrix. The aim of the present study was to examine the expression of Ang II and its type 1 (AT(1)) and type 2 (AT(2)) receptors in affected skin and dermal fibroblasts from patients with SSc and to study the role of Ang II in collagen production by SSc dermal fibroblasts.
Levels of Ang II in sera from SSc patients and normal subjects were measured by a solid-phase immobilized-epitope immunoassay. Expression of angiotensinogen (Angt) in the skin was evaluated by immunohistochemistry. Expression of Angt, AT(1), and AT(2) in cultured dermal fibroblasts was analyzed by reverse transcription-polymerase chain reaction and immunohistochemistry. Levels of type I procollagen produced by cultured dermal fibroblasts were measured by enzyme-linked immunosorbent assay.
Serum Ang II levels in patients with diffuse cutaneous SSc were significantly higher than those in patients with limited cutaneous SSc and in healthy donors. Immunohistochemical and immunoblotting analyses showed that Angt was present in skin from SSc patients, but not in normal skin. Angt messenger RNA (mRNA) was expressed in fibroblasts from patients with diffuse cutaneous SSc who had high levels of serum Ang II, but not in normal fibroblasts. AT(1) mRNA expression was found in both SSc and normal fibroblasts, whereas AT(2) mRNA was found only in SSc fibroblasts. Exogenous Ang II augmented the production of type I procollagen and transforming growth factor beta1 by cultured fibroblasts via activation of AT(1).
Aberrant Ang II production may be involved in tissue fibrosis through excessive production of the extracellular matrix components in SSc dermal fibroblasts. This suggests that the use of AT(1) receptor antagonists may be a novel strategy for the treatment of tissue fibrosis in SSc patients.
系统性硬化症（SSc）中的组织纤维化归因于皮肤病变中成纤维细胞产生的细胞外基质成分过度沉积。血管紧张素II（Ang II）是一种血管收缩肽，据报道由于诱导细胞外基质而具有促纤维化活性。本研究的目的是检测SSc患者受累皮肤和真皮成纤维细胞中Ang II及其1型（AT(1)）和2型（AT(2)）受体的表达，并研究Ang II在SSc真皮成纤维细胞胶原蛋白产生中的作用。
采用固相固定表位免疫分析法检测SSc患者和正常受试者血清中Ang II水平。通过免疫组织化学评估皮肤中血管紧张素原（Angt）的表达。通过逆转录-聚合酶链反应和免疫组织化学分析培养的真皮成纤维细胞中Angt、AT(1)和AT(2)的表达。采用酶联免疫吸附测定法检测培养的真皮成纤维细胞产生的I型前胶原水平。
弥漫性皮肤SSc患者的血清Ang II水平显著高于局限性皮肤SSc患者和健康供体。免疫组织化学和免疫印迹分析表明，Angt存在于SSc患者的皮肤中，而正常皮肤中不存在。血清Ang II水平高的弥漫性皮肤SSc患者的成纤维细胞中表达Angt信使核糖核酸（mRNA），而正常成纤维细胞中不表达。在SSc和成纤维细胞中均发现AT(1) mRNA表达，而AT(2) mRNA仅在SSc成纤维细胞中发现。外源性Ang II通过激活AT(1)增加培养的成纤维细胞产生I型前胶原和转化生长因子β1。
异常的Ang II产生可能通过SSc真皮成纤维细胞中细胞外基质成分的过度产生参与组织纤维化。这表明使用AT(1)受体拮抗剂可能是治疗SSc患者组织纤维化的一种新策略。
