Ka Shuk-Man, Huang Xiao-Ru, Lan Hui-Yao, Tsai Pei-Yi, Yang Shun-Min, Shui Hao-Ai, Chen Ann
Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, No. 325 Sec. 2 Cheng-Gung Road, Taipei, Taiwan, ROC.
J Am Soc Nephrol. 2007 Jun;18(6):1777-88. doi: 10.1681/ASN.2006080901. Epub 2007 May 2.
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-beta 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-kappaB activation (P < 0.01), thereby inhibiting alpha-smooth muscle actin; collagen I, III, and IV accumulation; and expression of inflammatory cytokines (IL-1beta 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.
自身免疫性新月体性肾小球肾炎的特征是严重的免疫反应，伴有肾小球新月体形成和肾脏纤维化。最近的研究表明，肾组织中Smad7的过表达可减轻大鼠残余肾的肾纤维化和炎症。然而，转化生长因子-β（TGF-β）/Smad信号通路在自身免疫性肾脏疾病中的潜在作用却很少受到关注。本研究验证了以下假说：通过Smad7过表达阻断TGF-β信号通路，可能对C57BL/6×DBA/2J F1杂交小鼠给予DBA/2J供体淋巴细胞诱导的自身免疫性新月体性肾小球肾炎小鼠模型具有治疗作用。利用超声微泡介导系统将Smad7基因转染至肾脏。结果显示，Smad7过表达在Smad2/3和核因子-κB（NF-κB）激活方面阻断了肾纤维化和炎症信号通路（P<0.01），从而抑制了α-平滑肌肌动蛋白；I、III和IV型胶原的积聚；以及炎性细胞因子（白细胞介素-1β和白细胞介素-6）、黏附分子/趋化因子（细胞间黏附分子-1、单核细胞趋化蛋白-1）和诱导型一氧化氮合酶的表达（均P<0.01）。白细胞浸润（CD4+细胞和巨噬细胞）也受到抑制（P<0.005）。严重的组织学损伤（肾小球新月体形成和肾小管间质损伤）以及包括蛋白尿在内的功能损伤均得到显著改善（均P<0.05）。本研究提供了重要证据，表明Smad7过表达可能对自身免疫性肾脏疾病具有治疗潜力。
