Kidney Proximal Tubular TLR9 Exacerbates Ischemic Acute Kidney Injury.
Kidney Proximal Tubular TLR9 Exacerbates Ischemic Acute Kidney Injury.
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DOI：
10.4049/jimmunol.1800211
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发表时间：
2018-08-01
期刊：
影响因子：
--
通讯作者：
Lee HT
中科院分区：
文献类型：
--
作者：
Han SJ;Li H;Kim M;Shlomchik MJ;Lee HT
肾脏TLR 9在缺血性急性肾损伤（阿基）中的作用尚不清楚。在此，我们检验了肾近端肾小管TLR 9激活通过促进肾小管上皮细胞凋亡和炎症而加重缺血性阿基的假设。为了检验这一假设，我们产生了在肾近端小管中缺乏TLR 9的小鼠（TLR 9 fl/fl PEPCK Cre小鼠）。与之前在整体TLR 9 KO小鼠中的研究相比，当与野生型（TLR 9 fl/fl）小鼠相比时，缺乏肾近端肾小管TLR 9的小鼠受到保护以免受肾缺血再灌注（IR）损伤，肾小管坏死、炎症（促炎细胞因子合成减少和中性粒细胞浸润）和细胞凋亡（DNA片段化和半胱天冬酶活化减少）减少。与此一致，选择性TLR 9激动剂ODN-1668加重了TLR 9 fl/fl小鼠中的肾IR损伤，但在肾近端肾小管TLR 9缺失小鼠中没有。此外，在培养的人和小鼠近曲小管细胞中，TLR 9选择性配体诱导NFκB活化、促炎细胞因子mRNA合成以及caspase活化。我们在此进一步证实，整体TLR 9缺乏对小鼠缺血性阿基没有影响。综上所述，我们的研究表明，肾近端肾小管TLR 9活化通过NFκB和caspase活化促进IR后肾小管炎症、凋亡以及坏死而加重缺血性阿基。我们的研究进一步表明TLR 9激活的复杂性，因为肾小管上皮细胞TLR 9促进细胞损伤和死亡，而其他细胞类型中的TLR 9信号传导可能促进细胞保护作用。
The role for kidney TLR9 in ischemic acute kidney injury (AKI) remains unclear. Here, we tested the hypothesis that renal proximal tubular TLR9 activation exacerbates ischemic AKI by promoting renal tubular epithelial apoptosis and inflammation. To test this hypothesis, we generated mice lacking TLR9 in renal proximal tubules (TLR9fl/fl PEPCK Cre mice). Contrasting previous studies in global TLR9KO mice, mice lacking renal proximal tubular TLR9 were protected against renal ischemia reperfusion (IR) injury with reduced renal tubular necrosis, inflammation (decreased pro-inflammatory cytokine synthesis and neutrophil infiltration) and apoptosis (decreased DNA fragmentation and caspase activation) when compared to wild type (TLR9fl/fl) mice. Consistent with this, a selective TLR9 agonist ODN-1668 exacerbated renal IR injury in TLR9fl/fl mice but not in renal proximal tubular TLR9 null mice. Furthermore, in cultured human and mouse proximal tubule cells, TLR9 selective ligands induced NFκB activation, pro-inflammatory cytokine mRNA synthesis as well as caspase activation. We further confirm here that global TLR9 deficiency had no impact on murine ischemic AKI. Taken together, our studies show that renal proximal tubular TLR9 activation exacerbates ischemic AKI by promoting renal tubular inflammation, apoptosis as well as necrosis after IR via NFκB and caspase activation. Our studies further suggest complex nature of TLR9 activation as renal tubular epithelial TLR9 promote cell injury and death whereas TLR9 signaling in other cell types may promote cytoprotective effects.
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DOI：
10.1159/000142934
发表时间：
2008
期刊：
Nephron. Experimental nephrology
影响因子：
--
作者：
Kinsey GR;Li L;Okusa MD
通讯作者：
Okusa MD
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.
影响因子：
3.7
作者：
Bakker PJ;Scantlebery AM;Butter LM;Claessen N;Teske GJ;van der Poll T;Florquin S;Leemans JC
通讯作者：
Leemans JC
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
影响因子：
6.1
作者：
Jo, SK;Sung, SA;Kim, HK
通讯作者：
Kim, HK