Ng Yee-Yung, Hou Chun-Cheng, Wang Wansheng, Huang Xiao R, Lan Hui Y
Section of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan.
Kidney Int Suppl. 2005 Apr(94):S83-91. doi: 10.1111/j.1523-1755.2005.09421.x.
Transforming growth factor-beta (TGF-beta) in renal fibrosis has been well studied, but little attention has been paid to the potential role of TGF-beta in the resolution of renal inflammation. We hypothesize that TGF-beta exerts its anti-inflammation properties by stimulating its negative signaling pathway involving Smad7.
A rat remnant kidney model was treated with a doxycycline-regulated Smad7 gene or control empty vector using an ultrasound-microbubble (Optison)-mediated system. Smad7 transgene expression within the kidney was tightly controlled by the addition of doxycycline in the daily drinking water. All animals were euthanized at week 4 for examination of inflammatory responses.
Real-time polymerase chain reaction (PCR) and immunohistochemistry revealed that gene transfer of Smad7 resulted in a substantial inhibition of interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha) expression (all P < 0.01 vs. control). This was associated with the attenuation of histology damage, proteinuria, serum creatinine, and an increase in creatinine clearance (all P < 0.05). In addition, overexpression of Smad7 significantly inhibited renal inflammation, including ICAM-1, iNOS, and accumulation of macrophages and T cells in both glomeruli and tubulointerstitium. Furthermore, gene transfer of Smad7 also substantially blocked nuclear factor kappa B (NFkappaB) activation in the rat remnant kidney (P < 0.01).
TGF-beta/Smad7 signaling plays a critical role in the resolution of renal inflammation in rat remnant kidney model. Inhibition of NFkappaB activation is a key mechanism by which Smad7 suppresses renal inflammation, which suggests a crosstalk pathway between NFkappaB and Smad7. The ability of Smad7 to inhibit renal inflammation indicates that ultrasound-microbubble-mediated Smad7 gene therapy may represents a new therapeutic strategy for glomerulonephritis.
转化生长因子-β（TGF-β）在肾纤维化中的作用已得到充分研究，但TGF-β在肾炎症消退中的潜在作用却很少受到关注。我们推测TGF-β通过刺激其涉及Smad7的负信号通路发挥抗炎特性。
使用超声微泡（Optison）介导的系统，用强力霉素调控的Smad7基因或对照空载体处理大鼠残肾模型。通过在日常饮水中添加强力霉素，严格控制肾脏内Smad7转基因的表达。所有动物在第4周处死，以检查炎症反应。
实时聚合酶链反应（PCR）和免疫组织化学显示，Smad7基因转移导致白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNFα）表达显著抑制（与对照组相比，均P < 0.01）。这与组织学损伤、蛋白尿、血清肌酐的减轻以及肌酐清除率的增加相关（均P < 0.05）。此外，Smad7的过表达显著抑制肾炎症，包括ICAM-1、诱导型一氧化氮合酶（iNOS）以及肾小球和肾小管间质中巨噬细胞和T细胞的积聚。此外，Smad7基因转移还显著阻断了大鼠残肾中核因子κB（NFκB）的激活（P < 0.01）。
TGF-β/Smad7信号通路在大鼠残肾模型的肾炎症消退中起关键作用。抑制NFκB激活是Smad7抑制肾炎症的关键机制之一，这提示了NFκB与Smad7之间的相互作用途径。Smad7抑制肾炎症的能力表明，超声微泡介导的Smad7基因治疗可能代表了一种治疗肾小球肾炎的新策略。
