Treatment with anti-TGF-β antibody ameliorates chronic progressive nephritis by inhibiting Smad/TGF-β signaling
Treatment with anti-TGF-β antibody ameliorates chronic progressive nephritis by inhibiting Smad/TGF-β signaling
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DOI：
10.1111/j.1523-1755.2004.00393.x
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发表时间：
2004-01-01
影响因子：
19.6
通讯作者：
Hishida, A
中科院分区：
文献类型：
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作者：
Fukasawa, H;Yamamoto, T;Hishida, A
背景虽然抗转化生长因子-β（TGF-β）抗体（α T）的短期治疗已被证明可以预防早期肾小球病变，但其长期作用和分子机制，包括细胞内信号传导，仍然知之甚少。我们研究了T治疗是否能预防肾功能不全和纤维化，以及是否能影响慢性进行性抗胸腺细胞血清（ATS）肾炎大鼠的TGF-β/Smad信号通路。从第7天到第35天，用T或对照免疫球蛋白（IG）G每周两次治疗肾炎和非肾炎大鼠4周（每组，N = 21）。通过免疫组化、Western印迹和/或实时逆转录聚合酶链反应（RT-PCR）检测肾脏病变和皮质TGF-β 1、TGF-β 2、TGF-β 3、II型TGF-β受体（TbetaRII）、Smads、I型胶原和纤溶酶原激活物抑制剂-1的表达。用电泳迁移率变动法研究肾皮质细胞核中Smad 3与Smad-binding element（SBE）的结合。肾病大鼠出现大量蛋白尿、肾功能不全和细胞外基质沉积增加，导致肾纤维化。皮质TGF-β 1、TGF-β 2、TbetaRII和Smad 2的表达水平增加，但TGF-β 3、Smad 3和Smad 4的表达水平没有增加。磷酸化Smad 2/3在肾小球和肾小管细胞核中的表达和优先定位，以及Smad 3-SBE复合物形成活性也增加。4周的alphaT治疗导致慢性进展性ATS肾炎在8周时显著改善。在慢性进行性ATS肾炎中，TGF-β/Smad信号上调。通过alphaT阻断TGF-β至少部分地通过抑制活化的TGF-β/Smad信号传导来抑制肾瘢痕形成的进展。
Background. Although short-term treatment with antitransforming growth factor-beta (TGF-beta) antibody (alphaT) has been shown to prevent early glomerular lesions, its long-term effects and molecular mechanisms, including intracellular signaling, remain poorly understood. We examined whether a T treatment induces prevention of renal insufficiency and fibrosis, and affects the TGF-beta/Smad signaling pathway in rats with chronic progressive anti-thymocyte serum (ATS) nephritis induced by repeated ATS injections on days 0 and 7.Methods. Nephritic and non-nephritic rats were treated with either a T or control immunoglobulin (Ig) G twice weekly for 4 weeks from days 7 to 35 (each group, N = 21). Renal lesions and cortical expression of TGF-beta1, TGF-beta2, TGF-beta3, type II TGF-beta receptor (TbetaRII), Smads, type I collagen, and plasminogen activator inhibitor-1 were examined by immunohistochemistry, Western blot, and/or real-time reverse transcription polymerase chain reaction (RT-PCR). The binding of Smad3 in renal cortical cell nuclei to the Smad-binding element (SBE) was investigated by the electrophoretic mobility shift assay.Results. Nephritic rats developed heavy proteinuria, renal insufficiency, and increased extracellular matrix deposition resulting in renal fibrosis. Cortical expression levels of TGF-beta1, TGF-beta2, TbetaRII, and Smad2, but not TGF-beta3, Smad3, and Smad4 were increased. Expression and preferential localization of phosphorylated Smad2/3 in the glomerular and tubular cell nuclei, and Smad3-SBE complex-forming activity were also increased. Four-week alphaT treatment resulted in marked amelioration of chronic progressive ATS nephritis at 8 weeks.Conclusion. In chronic progressive ATS nephritis, the TGF-beta/Smad signaling was up-regulated. TGF-beta blockade by alphaT suppressed the progression of renal scarring, at least in part, via inhibition of activated TGF-beta/Smad signaling.