Nox2 is a mediator of chronic CsA nephrotoxicity.
Nox2 is a mediator of chronic CsA nephrotoxicity.
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DOI：
10.1111/j.1600-6143.2012.04081.x
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发表时间：
2012-08
期刊：
影响因子：
--
通讯作者：
Torrealba JR
中科院分区：
文献类型：
--
作者：
Djamali A;Reese S;Hafez O;Vidyasagar A;Jacobson L;Swain W;Kolehmainen C;Huang L;Wilson NA;Torrealba JR
我们推测，典型的吞噬性NADPH氧化酶Nox2在钙调磷酸酶抑制剂（CNI）诱导的肾纤维化中起重要作用。我们在体外、动物和人类研究中验证了这一假设。环孢素A （CsA）和他克莫司（TAC）与NRK52E细胞中较高水平的Nox2 mRNA和上皮到间质转化（EMT）相关。CsA增加Nox2、α-SMA和磷酸化p38mapk、Smad3和NFκB蛋白。在TGF-β1敲除细胞中，Nox2的上调和EMT均受到抑制，提示Nox2的激活需要TGF-β1。免疫印迹分析显示，高剂量CsA处理的Fisher344大鼠小管间质Nox2升高，α-SMA、磷酸化Smad3和硝基酪氨酸升高。同时给药罗布麻或二苯基碘对Nox2的抑制作用与纤维生成减少有关。我们用高剂量CsA治疗野生型和Nox2 null （B6.129S-CybbTm1Din/J）小鼠，验证了这些发现。Western blot分析证实，csa敲除小鼠中Nox2缺失，α-SMA和4-羟基壬烯醛水平显著降低。这些发现具有临床意义，因为15例肝移植肾小管间质活检证实慢性CsA或TAC肾毒性患者肾小管间质Nox2和α-SMA升高。总之，特异性的Nox2抑制策略可能改善实体器官移植的慢性CNI肾毒性。
We hypothesized that Nox2, the classical phagocytic NADPH oxidase, plays an important role in calcineurin inhibitor (CNI)-induced renal fibrosis. We tested this hypothesis in vitro, in animal and in human studies. Cyclosporine A (CsA) and tacrolimus (TAC) were associated with greater levels of Nox2 mRNA and epithelial to mesenchymal transition (EMT) in NRK52E cells. CsA increased Nox2, α-SMA and phosphorylated-p38MAPK, Smad3, and NFκB proteins. Nox2 upregulation and EMT were inhibited in TGF-β1 knockout cells suggesting that TGF-β1 is required for Nox2 activation. Fisher344 rats treated with high dose CsA showed increased Nox2 in the tubulointerstitium and greater Nox2, α-SMA, phosphorylated Smad3 and nitrotyrosine by immunoblot analyses. Inhibition of Nox2 by coadministration of apocynin or diphenyleneiodonium was associated with reduced fibrogenesis. We validated these findings by treating wild type and Nox2 null (B6.129S-CybbTm1Din/J) mice with high dose CsA. Western blot analyses confirmed the absence of Nox2 and significantly lower levels of α-SMA and 4-hydroxynonenal in CsA-treated knockout mice. These findings were clinically relevant since Nox2 and α-SMA were increased in the tubulointerstitium of kidneys from 15 liver transplant recipients with biopsy-confirmed chronic CsA or TAC nephrotoxicity. In conclusion, specific Nox2 inhibition strategies may improve chronic CNI nephrotoxicity in solid organ transplantation.
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影响因子：
6.2
作者：
Khanna, AK;Cairns, VR;Hosenpud, JD
通讯作者：
Hosenpud, JD
影响因子：
6.2
作者：
Copeland, Justin W. G. V.;Beaumont, Brent W.;Pilmore, Helen L.
通讯作者：
Pilmore, Helen L.
DOI：
10.1111/j.1600-6143.2008.02463.x
发表时间：
2009-01
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Djamali A;Vidyasagar A;Adulla M;Hullett D;Reese S
通讯作者：
Reese S
影响因子：
3.7
作者：
Levenson, Richard M.
通讯作者：
Levenson, Richard M.
影响因子：
6.2
作者：
Djamali A;Vidyasagar A;Yagci G;Huang LJ;Reese S
通讯作者：
Reese S