Han Sang Jun, Williams Ryan M, D'Agati Vivette, Jaimes Edgar A, Heller Daniel A, Lee H Thomas
Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York, USA.
Department of Molecular Pharmacology & Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Department of Biomedical Engineering, City College of New York, New York, New York, USA.
Kidney Int. 2020 Jul;98(1):76-87. doi: 10.1016/j.kint.2020.01.036. Epub 2020 Feb 22.
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.
我们开发了一种针对缺血性急性肾损伤的创新疗法，在遭受肾缺血再灌注损伤的小鼠中，实现了对肾脏有识别能力的靶向递送选择性Toll样受体9（TLR9）拮抗剂。我们之前的研究表明，肾近端小管TLR9缺陷的小鼠对肾缺血再灌注损伤具有保护作用，这表明肾近端小管TLR9在引发缺血性急性肾损伤中起关键作用。在此，我们使用了基于聚合物的300 - 400纳米中尺度纳米颗粒，静脉注射后可定位于肾小管。小鼠在接受包裹有选择性TLR9拮抗剂（未甲基化的CpG寡核苷酸ODN2088）的中尺度纳米颗粒或包裹阴性对照寡核苷酸的中尺度纳米颗粒后，接受假手术或30分钟的肾缺血再灌注损伤。在肾缺血前6小时、再灌注时或再灌注后1.5小时用包裹的TLR9拮抗剂治疗的小鼠对缺血性急性肾损伤具有保护作用。与阴性对照纳米颗粒处理的小鼠相比，包裹ODN2088的纳米颗粒减轻了肾小管坏死、炎症，减少了促炎细胞因子的合成、中性粒细胞和巨噬细胞浸润以及细胞凋亡，减少了DNA片段化和半胱天冬酶3/8的激活。综上所述，我们的研究进一步表明，肾近端小管TLR9的激活通过促进缺血再灌注后肾小管炎症、细胞凋亡和坏死，加剧了缺血性急性肾损伤。因此，我们的研究表明，使用基于中尺度纳米颗粒的药物递送选择性地靶向肾小管TLR9，对缺血性急性肾损伤具有潜在的有前景的治疗方法。
