Delivery of AAV2-CYP2J2 protects remnant kidney in the 5/6-nephrectomized rat via inhibition of apoptosis and fibrosis.
Delivery of AAV2-CYP2J2 protects remnant kidney in the 5/6-nephrectomized rat via inhibition of apoptosis and fibrosis.
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AAV2-CYP2J2 的递送通过抑制细胞凋亡和纤维化来保护 5/6 肾切除大鼠的残肾。
DOI：
10.1089/hum.2011.135
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发表时间：
2012-01
影响因子：
4.2
通讯作者：
Wang DW
中科院分区：
文献类型：
--
作者：
Zhao G;Tu L;Li X;Yang S;Chen C;Xu X;Wang P;Wang DW
细胞色素P450环氧合酶CYP 2 J2将花生四烯酸转化为四种区域异构体环氧二十碳三烯酸（E3），E3在肾脏中含量很高，被认为具有肾脏保护作用。越来越多的证据表明，雌二醇在调节肾脏和心血管功能方面具有重要作用。此外，已证实Eclampin发挥多种生物活性，包括有效的血管舒张;纤维蛋白溶解特性;以及抗凋亡和促有丝分裂作用。在本研究中，我们研究了通过重组腺相关病毒（rAAV）过表达CYP 2 J2对慢性肾功能衰竭大鼠5/6肾切除（5/6-Nx）模型肾损伤的保护作用。rAAV-CYP 2 J2基因体内递送增加了EET的产生;减弱了血压的升高;并降低了蛋白尿、血清肌酐和血尿素氮的水平。形态学分析表明，rAAV-CYP 2 J2基因递送减少了5/6肾切除术诱导的肾小球硬化、肾小管扩张、管腔蛋白管型形成和肾小管间质纤维化。rAAV-CYP 2 J2基因递送还显著降低胶原I和IV沉积，以及通过TUNEL染色检测的肾细胞凋亡、半胱天冬酶-3活性和线粒体膜电位（Δ Δ m）的损失。此外，rAAV-CYP 2 J2基因递送调节蛋白质表达水平，包括转化生长因子（TGF）-β（1）/SMAD;基质金属蛋白酶（MMPs）;丝裂原活化蛋白激酶（MAPK）;以及凋亡相关蛋白Bax、Bcl-2和Bcl-x（L）。总之，这些发现表明，rAAV-CYP 2 J2基因递送可以通过调节蛋白质表达（包括TGF-β（1）/SMADs、MMPs、MAPKs和凋亡相关蛋白）来抑制凋亡和纤维化，从而保护5/6-Nx大鼠的残肾免受肾损伤。
The cytochrome P450 epoxygenase, CYP2J2, converts arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EETs), which are highly abundant in the kidney and considered renoprotective. Accumulating evidence suggests that EETs are important in regulating renal and cardiovascular function. Further, EETs have been confirmed to exert diverse biological activities including potent vasodilation; fibrinolytic properties; and antiinflammatory, antiapoptotic, and mitogenic effects. In the current study, we investigated the effects of overexpression of CYP2J2 via recombinant adeno-associated virus (rAAV) in protection against renal damage in a rat 5/6 nephrectomy (5/6-Nx) model of chronic renal failure. The rAAV-CYP2J2 gene delivery in vivo increased EET generation; attenuated the rise in blood pressure; and reduced the levels of proteinuria, serum creatinine, and blood urea nitrogen. Morphological analysis indicated that rAAV-CYP2J2 gene delivery reduced 5/6 nephrectomy-induced glomerular sclerosis, tubular dilatation, luminal protein cast formation, and tubulointerstitial fibrosis. rAAV-CYP2J2 gene delivery also significantly lowered collagen I and IV deposition, as well as renal cell apoptosis detected by TUNEL staining, caspase-3 activity, and the loss of mitochondrial membrane potential (ΔΨ(m)). Furthermore, rAAV-CYP2J2 gene delivery regulated the level of protein expression including transforming growth factor (TGF)-β(1)/SMADs; matrix metalloproteinases (MMPs); mitogen-activated protein kinases (MAPKs); and apoptosis-related proteins Bax, Bcl-2, and Bcl-x(L). Together, these findings demonstrated that rAAV-CYP2J2 gene delivery can protect remnant kidney against renal injury in 5/6-Nx rats by inhibiting apoptosis and fibrosis via regulation of protein expression including TGF-β(1)/SMADs, MMPs, MAPKs, and apoptosis-related proteins.
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DOI：
10.1074/jbc.272.19.12551
发表时间：
1997-05
期刊：
The Journal of Biological Chemistry
影响因子：
--
作者：
Shu Wu;Weina Chen;E. Murphy;S. Gabel;K. Tomer;J. Foley;C. Steenbergen;J. Falck;C. Moomaw;D. Zeldin
通讯作者：
Shu Wu;Weina Chen;E. Murphy;S. Gabel;K. Tomer;J. Foley;C. Steenbergen;J. Falck;C. Moomaw;D. Zeldin
影响因子：
6.5
作者：
J. Capdevila;J. Falck;Raymond C. Harris
通讯作者：
J. Capdevila;J. Falck;Raymond C. Harris
影响因子：
12.4
作者：
Zincarelli, Carmela;Soltys, Stephen;Rabinowitz, Joseph E.
通讯作者：
Rabinowitz, Joseph E.
影响因子：
15.9
作者：
Nakagawa, Kiyoshi;Holla, Vijaykumar R.;Capdevila, Jorge H.
通讯作者：
Capdevila, Jorge H.
影响因子：
3.6
作者：
D. Zeldin;J. Foley;S. Goldsworthy;M. E. Cook;J. Boyle;Jixiang Ma;C. Moomaw;K. Tomer;C. Steenbergen;Shu Wu
通讯作者：
D. Zeldin;J. Foley;S. Goldsworthy;M. E. Cook;J. Boyle;Jixiang Ma;C. Moomaw;K. Tomer;C. Steenbergen;Shu Wu