Mycophenolic acid may delay allograft fibrosis by inhibiting transforming growth factor-beta1-induced activation of Nox-2 through the nuclear factor-kappaB pathway.
Mycophenolic acid may delay allograft fibrosis by inhibiting transforming growth factor-beta1-induced activation of Nox-2 through the nuclear factor-kappaB pathway.
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DOI：
10.1097/tp.0b013e3181e6ae0a
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发表时间：
2010-08-27
期刊：
影响因子：
6.2
通讯作者：
Reese S
中科院分区：
文献类型：
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作者：
Djamali A;Vidyasagar A;Yagci G;Huang LJ;Reese S
我们评估了肾小管Nox-2在肾移植中上皮间质转化（EMT）发病机制中的作用。我们在伴有肾小管间质纤维化（未另作说明）的人肾同种异体移植物（IFTANOS）、Fisher至刘易斯大鼠移植模型和正常大鼠肾上皮细胞TGF-β1诱导EMT的体外模型（NRK 52 E）中研究了这一问题。我们首次证明，在肾移植受者中，使用钙调磷酸酶抑制剂、霉酚酸和泼尼松与IFTANOS的肾小管中Nox-2和α-SMA增加，提示EMT（n=6）。接下来，我们检查了同基因移植物中的Nox-2表达和纤维形成;用MPA 40 mg/kg/24 h处理的同种异体移植物和未处理的同种异体移植物6个月（每组n=14）。Nox-2、α-SMA和E-cadherin的免疫荧光和免疫组织化学研究表明，与IFTANOS患者相似，大鼠同种异体移植物中Nox-2和α-SMA的小管间质染色更强。MPA治疗阻止了这些变化。检测Nox-2信号（磷酸化NF-κB）、氧化还原信号（磷酸化Smad 2）和纤维化（α-SMA和纤连蛋白）的免疫印迹分析表明，MPA处理阻止了Nox-2的上调，抑制了p-NF-κB和p-Smad 2，并下调了α-SMA和纤连蛋白水平。最后，我们在体外检测了Nox-2信号通路，证实MPA在TGF-β1诱导的NRK 52 E细胞EMT过程中抑制磷酸化NF-κB、Nox-2、磷酸化Smad 2和α-SMA，同时降低Nox-2、vimentin和Fibronectin的mRNA水平。MPA可能通过NF-κB通路下调肾小管上皮细胞的Nox-2活化和EMT，这表明该药物具有独立于其免疫抑制特性的新作用。
We evaluated the role of renal tubular Nox-2 in the pathogenesis of epithelial-to-mesenchymal transition (EMT) in kidney allografts. We examined this question in human kidney allografts with tubulointerstitial fibrosis not otherwise specified (IFTANOS), in the Fisher to Lewis rat transplant model and in the in vitro model of TGF-β1-induced EMT in normal rat kidney epithelial cells (NRK52E). We first demonstrated that Nox-2 and α-SMA were increased in renal tubules from kidney transplant recipients on calcineurin inhibitors, mycophenolic acid and prednisone with IFTANOS, suggestive of EMT (n=6). Next we examined Nox-2 expression and fibrogenesis in syngeneic transplants; allogeneic transplants treated with MPA 40 mg/kg/24h and untreated allogeneic transplants for 6 months (n=14 in each group). Immunofluorescent and immunohistochemical studies for Nox-2, α-SMA and E-cadherin showed that similar to patients with IFTANOS, rat allografts had greater tubulointerstitial staining for Nox-2 and α-SMA. MPA therapy prevented these changes. Immunoblot analyses examining Nox-2 signaling (phospho-NF-κB), redox signaling (phospho-smad2) and fibrosis (α-SMA and fibronectin) demonstrated that MPA treatment prevented the upregulation of Nox-2, inhibited p-NF-κB and p-smad2 and downregulated α-SMA and fibronectin levels. Last, we examined Nox-2 signaling in vitro and confirmed that MPA inhibited phospho-NF-κB, Nox-2, phospho-smad2 and α-SMA during TGF-β1-induced EMT of NRK52E cells while reducing Nox-2, vimentin and Fibronectin mRNA levels. MPA may downregulate Nox-2 activation and EMT via the NF-κB pathway in tubular epithelial cells suggesting a novel role for this drug independent of its immunosuppressive properties.