Smad7 gene therapy ameliorates an autoimmune crescentic glomerulonephritis in mice
Smad7 gene therapy ameliorates an autoimmune crescentic glomerulonephritis in mice
复制标题
DOI：
10.1681/asn.2006080901
复制
发表时间：
2007-06-01
影响因子：
13.6
通讯作者：
Chen, Ann
中科院分区：
文献类型：
--
作者：
Ka, Shuk-Man;Huang, Xiao-Ru;Chen, Ann
自身免疫性新月体肾小球肾炎是一种以严重的免疫反应为特征的疾病，伴有肾小球新月体形成和肾脏纤维化。最近的研究表明，肾脏Smad 7的过表达可以减轻大鼠残肾的肾纤维化和炎症。然而，很少有人关注TGF-β/Smad信号在自身免疫性肾病中的潜在作用。本研究验证了这样的假设，即通过Smad 7的过表达阻断TGF-β信号传导可能对C57 BL/6 x DBA/2 J F1杂交小鼠通过给予DBA/2 J供体淋巴细胞诱导的自身免疫性新月体肾小球肾炎小鼠模型具有治疗效果。利用超声微泡介导法将Smad 7基因转染入大鼠肾脏。结果显示，Smad 7的过表达阻断了肾纤维化和炎症途径中的Smad 2/3和NF-κ B活化（P < 0.01），从而抑制α-平滑肌肌动蛋白;胶原I、III和IV积累;和炎症细胞因子的表达（IL-1 β和IL-6）、粘附分子/趋化因子（细胞间粘附分子-1、单核细胞趋化蛋白-1）和诱导型一氧化氮合酶（均P < 0.01）。白细胞浸润（CD 4+细胞和巨噬细胞）也受到抑制（P < 0.005）。严重的组织学损害（肾小球新月体形成和肾小管间质损伤）和功能损害（包括蛋白尿）明显改善（均P < 0.05）。这项研究提供了重要的证据，Smad 7的过表达可能具有治疗自身免疫性肾病的潜力。
Autoimmune crescentic glomerulonephritis is characterized by severe immune response with glomerular crescentic formation and fibrosis in the kidney. Recent studies indicate that overexpression of renal Smad7 attenuates both renal fibrosis and inflammation in rat remnant kidney. However, little attention has been paid to the potential role of TGF-beta/Smad signaling in autoimmune kidney disease. This study tested the hypothesis that blocking TGF-P signaling by overexpression of Smad7 may have a therapeutic effect in a mouse model of autoimmune crescentic glomerulonephritis that was induced in C57BL/6 x DBA/2J F1 hybrid mice by giving DBA/2J donor lymphocytes. Smad7 gene was transfected into the kidney using the ultrasound-microbubble-mediated system. Results showed that overexpression of Smad7 blocked both renal fibrosis and inflammatory pathways in terms of Smad2/3 and NF-kappa B activation (P < 0.01), thereby inhibiting alpha-smooth muscle actin; collagen I, III, and IV accumulation; and expression of inflammatory cytokines (IL-1 beta and IL-6), adhesion molecule/ chemokine (intercellular adhesion molecule-1, monocyte chemoattractant protein-1), and inducible nitric oxide synthase (all P < 0.01). Leukocyte infiltration (CD4(+) cells and macrophages) was also suppressed (P < 0.005). Severe histologic damage (glomerular crescent formation and tubulointerstitial injury) and functional injury including proteinuria were significantly improved (all P < 0.05). This study provides important evidence that overexpression of Smad7 may have therapeutic potential for autoimmune kidney disease.