霉酚酸可能通过核因子-κB 通路抑制转化生长因子-β1诱导的 Nox-2 激活来延迟移植物纤维化。
Mycophenolic acid may delay allograft fibrosis by inhibiting transforming growth factor-beta1-induced activation of Nox-2 through the nuclear factor-kappaB pathway.
机构信息
Department of Medicine, University of Wisconsin Madison SMPH, Madison, WI, USA.
出版信息
Transplantation. 2010 Aug 27;90(4):387-93. doi: 10.1097/TP.0b013e3181e6ae0a.
BACKGROUND
We evaluated the role of renal tubular Nox-2 in the pathogenesis of epithelial-to-mesenchymal transition (EMT) in kidney allografts.
METHODS
We examined this question in the human kidney allografts with interstitial fibrosis and tubular atrophy not otherwise specified (IFTANOS), in the Fisher to Lewis rat transplant model, and in the in vitro model of transforming growth factor-beta1-induced EMT in normal rat kidney epithelial cells (NRK52E).
RESULTS
We first demonstrated that Nox-2 and alpha-smooth muscle actin (SMA) were increased in renal tubules from kidney transplant recipients on calcineurin inhibitors, mycophenolic acid (MPA), 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 per 24 hr, and untreated allogeneic transplants for 6 months (n=14 in each group). Immunofluorescent and immunohistochemical studies for Nox-2, alpha-SMA, and E-cadherin showed that similar to patients with IFTANOS, rat allografts had greater tubulointerstitial staining for Nox-2 and alpha-SMA. MPA therapy prevented these changes. Immunoblot analyses examining Nox-2 signaling (phospho-nuclear factor [NF]-kappaB), redox signaling (phospho-smad2), and fibrosis (alpha-SMA and fibronectin) demonstrated that MPA treatment prevented the up-regulation of Nox-2, inhibited p-NF-kappaB and p-smad2, and down-regulated alpha-SMA and fibronectin levels. Finally, we examined Nox-2 signaling in vitro and confirmed that MPA inhibited phospho-NF-kappaB, Nox-2, phospho-smad2, and alpha-SMA during transforming growth factor-beta1-induced EMT of NRK52E cells while reducing Nox-2, vimentin, and fibronectin mRNA levels.
CONCLUSIONS
MPA may down-regulate Nox-2 activation and EMT through the NF-kappaB pathway in the tubular epithelial cells, suggesting a novel role for this drug independent of its immunosuppressive properties.
背景
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。
方法
我们在非特定间质纤维化和肾小管萎缩（IFTANOS）的人类肾移植、Fisher 到 Lewis 大鼠移植模型以及转化生长因子-β1 诱导的正常大鼠肾上皮细胞（NRK52E） EMT 的体外模型中研究了这个问题。
结果
我们首先证明，在接受钙调神经磷酸酶抑制剂、霉酚酸（MPA）和泼尼松治疗的肾移植患者中，肾移植中 Nox-2 和α-平滑肌肌动蛋白（SMA）在肾小管中增加，提示 EMT（n=6）。接下来，我们检查了同基因移植、接受 MPA 40mg/kg/24 小时的同种异体移植和未治疗的同种异体移植 6 个月（每组 14 例）中的 Nox-2 表达和纤维化。Nox-2、α-SMA 和 E-钙粘蛋白的免疫荧光和免疫组化研究表明，与 IFTANOS 患者相似，大鼠同种异体移植中肾小管间质 Nox-2 和α-SMA 的染色更强。MPA 治疗可预防这些变化。免疫印迹分析检查 Nox-2 信号（磷酸核因子[NF]-κB）、氧化还原信号（磷酸化 smad2）和纤维化（α-SMA 和纤维连接蛋白）表明，MPA 治疗可防止 Nox-2 的上调，抑制 p-NF-κB 和 p-smad2，并下调α-SMA 和纤维连接蛋白水平。最后，我们在体外研究了 Nox-2 信号，并证实 MPA 抑制了转化生长因子-β1 诱导的 NRK52E 细胞 EMT 过程中的磷酸化 NF-κB、Nox-2、磷酸化 smad2 和α-SMA，同时降低了 Nox-2、波形蛋白和纤维连接蛋白的 mRNA 水平。
结论
MPA 可能通过 NF-κB 途径下调肾小管上皮细胞中 Nox-2 的激活和 EMT，提示该药物具有独立于其免疫抑制特性的新作用。
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