NFAT5 is protective against ischemic acute kidney injury.
NFAT5 is protective against ischemic acute kidney injury.
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DOI：
10.1161/hypertensionaha.113.02476
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发表时间：
2014-03
期刊：
影响因子：
--
通讯作者：
Ferreri NR
中科院分区：
文献类型：
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作者：
Hao S;Bellner L;Zhao H;Ratliff BB;Darzynkiewicz Z;Vio CP;Ferreri NR
NFAT5是一种保护肾脏免受高渗应激的转录因子，也在缺氧时被激活。我们假设NFAT5减轻了缺血再灌注损伤（IRI）引起的肾损害的程度。小鼠单侧夹持左肾蒂30分钟后再灌注IRI。再灌注3 h后，对侧肾和夹紧肾的NFAT5 mRNA水平相似。然而，48小时后，髓外和髓厚升肢（mTAL）小管中NFAT5 mRNA的积累增加了约3倍。NFAT1水平在3小时时升高，但在48小时时没有进一步升高。然后在诱导IRI之前，小鼠通过静脉注射慢病毒shRNA结构来沉默NFAT5 （EGFP-U6- n5 -ex8）或对照载体（EGFP-U6）预处理72小时。NGAL和Kim-1 mRNA水平在IRI后升高，在NFAT5敲除后进一步升高，提示NFAT5沉默加重了IRI期间的肾损害。相比之下，NFAT1的沉默对NGAL或Kim-1 mRNA的水平没有影响。H&E染色显示NFAT5沉默时肾上皮细胞斑片状剥蚀和肾小管扩张。NFAT5敲低后，夹紧肾外髓和内髓中tunel阳性细胞的数量增加了近2倍，并与caspase-3阳性细胞的数量增加有关。总的来说，这些数据表明NFAT5是限制IRI引起的肾损害的保护机制的一部分。
NFAT5 is a transcription factor that protects the kidney from hypertonic stress and also is activated by hypoxia. We hypothesized that NFAT5 mitigates the extent of renal damage induced by ischemia-reperfusion injury (IRI). Mice were subjected to IRI by unilateral clamping of the left renal pedicle for 30 min followed by reperfusion. After 3 h of reperfusion, the level of NFAT5 mRNA was similar in contralateral and clamped kidneys. However, after 48 h NFAT5 mRNA accumulation increased approximately three-fold in both outer medulla and medullary thick ascending limb (mTAL) tubules. NFAT1 levels were elevated at 3 h but did not increase further at 48 h. Mice were then either pretreated for 72 h with an intrarenal injection of a lentivirus shRNA construct to silence NFAT5 (EGFP-U6-N5-ex8), or a control vector (EGFP-U6) before induction of IRI. NGAL and Kim-1 mRNA levels increased after IRI and further increased after knockdown of NFAT5, suggesting that silencing of NFAT5 exacerbates renal damage during IRI. In contrast, silencing of NFAT1 had no effect on the levels of NGAL or Kim-1 mRNA. H&E staining revealed patchy denudation of renal epithelial cells and tubular dilation when NFAT5 was silenced. The number of TUNEL-positive cells in the outer and inner medulla of the clamped kidney increased nearly 2-fold after knockdown of NFAT5 and was associated with an increase in the number of caspase-3 positive cells. Collectively, the data suggest that NFAT5 is part of a protective mechanism that limits renal damage induced by IRI.