Selective nanoparticle-mediated targeting of renal tubular Toll-like receptor 9 attenuates ischemic acute kidney injury.
Selective nanoparticle-mediated targeting of renal tubular Toll-like receptor 9 attenuates ischemic acute kidney injury.
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DOI：
10.1016/j.kint.2020.01.036
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发表时间：
2020-07
影响因子：
19.6
通讯作者：
Lee HT
中科院分区：
文献类型：
--
作者：
Han SJ;Williams RM;D'Agati V;Jaimes EA;Heller DA;Lee HT
我们开发了一种创新的治疗缺血性急性肾损伤的方法，在肾缺血再灌注损伤的小鼠中识别选择性Toll样受体9（TLR 9）拮抗剂的肾靶向递送。我们之前的研究表明，肾近端肾小管TLR 9缺陷的小鼠可以免受肾缺血再灌注损伤，这表明肾近端肾小管TLR 9在产生缺血性急性肾损伤中发挥着关键作用。在本文中，我们使用了300-400 nm基于聚合物的介观纳米颗粒，其在静脉内注射后定位于肾小管。在接受用选择性TLR 9拮抗剂（未甲基化的CpG寡核苷酸ODN 2088）包封的中尺度纳米颗粒或包封阴性对照寡核苷酸的中尺度纳米颗粒后，使小鼠经受假手术或30分钟肾缺血和再灌注损伤。在肾缺血前6小时、再灌注时或再灌注后1.5小时用包封的TLR 9拮抗剂处理的小鼠被保护免于缺血性急性肾损伤。ODN 2088包封的纳米颗粒减轻肾小管坏死、炎症，减少促炎细胞因子合成。与阴性对照纳米颗粒处理的小鼠相比，中性粒细胞和巨噬细胞浸润和凋亡减少，DNA片段化和半胱天冬酶3/8活化减少。总之，我们的研究进一步表明，肾近端肾小管TLR 9激活通过促进缺血再灌注后肾小管炎症、凋亡和坏死而加重缺血性急性肾损伤。因此，我们的研究表明，一个潜在的有前途的治疗缺血性急性肾损伤与选择性肾小管靶向TLR 9使用中尺度纳米颗粒为基础的药物输送。
We developed an innovative therapy for ischemic acute kidney injury with discerning kidney-targeted delivery of a selective Toll-like receptor 9 (TLR9) antagonist in mice subjected to renal ischemia reperfusion injury. Our previous studies showed that mice deficient in renal proximal tubular TLR9 were protected against renal ischemia reperfusion injury demonstrating a critical role for renal proximal tubular TLR9 in generating ischemic acute kidney injury. Herein, we used 300–400 nm polymer-based mesoscale nanoparticles that localize to the renal tubules after intravenous injection. Mice were subjected to sham surgery or 30 minutes renal ischemia and reperfusion injury after receiving mesoscale nanoparticles encapsulated with a selective TLR9 antagonist (unmethylated CpG oligonucleotide ODN2088) or mesoscale nanoparticles encapsulating a negative control oligonucleotide. Mice treated with the encapsulated TLR9 antagonist either six hours before renal ischemia, at the time of reperfusion or 1.5 hours after reperfusion were protected against ischemic acute kidney injury. The ODN2088-encapsulated nanoparticles attenuated renal tubular necrosis, inflammation, decreased proinflammatory cytokine synthesis. neutrophil and macrophage infiltration and apoptosis, decreased DNA fragmentation and caspase 3/8 activation when compared to the negative control nanoparticle treated mice. Taken together, our studies further suggest that renal proximal tubular TLR9 activation exacerbates ischemic acute kidney injury by promoting renal tubular inflammation, apoptosis and necrosis after ischemia reperfusion. Thus, our studies suggest a potential promising therapy for ischemic acute kidney injury with selective kidney tubular targeting of TLR9 using mesoscale nanoparticle-based drug delivery.
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影响因子：
13.5
作者：
Bamboat, Zubin M.;Balachandran, Vinod P.;Ocuin, Lee M.;Obaid, Hebroon;Plitas, George;DeMatteo, Ronald P.
通讯作者：
DeMatteo, Ronald P.
Toll样受体9可被内源线粒体DNA激活诱导足细胞凋亡
影响因子：
4.6
作者：
Bao W;Xia H;Liang Y;Ye Y;Lu Y;Xu X;Duan A;He J;Chen Z;Wu Y;Wang X;Zheng C;Liu Z;Shi S
通讯作者：
Shi S
DOI：
10.4049/jimmunol.1800211
发表时间：
2018-08-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Han SJ;Li H;Kim M;Shlomchik MJ;Lee HT
通讯作者：
Lee HT
影响因子：
82.9
作者：
Chen, Chun-Jen;Kono, Hajime;Rock, Kenneth L.
通讯作者：
Rock, Kenneth L.
影响因子：
9.8
作者：
Hilmi, I. A.;Damian, D.;Kellum, J. A.
通讯作者：
Kellum, J. A.