Tamm-Horsfall protein translocates to the basolateral domain of thick ascending limbs, interstitium, and circulation during recovery from acute kidney injury
Tamm-Horsfall protein translocates to the basolateral domain of thick ascending limbs, interstitium, and circulation during recovery from acute kidney injury
复制标题
DOI：
10.1152/ajprenal.00543.2012
复制
发表时间：
2013-04-01
影响因子：
4.2
通讯作者：
Wu, Xue-Ru
中科院分区：
文献类型：
--
作者：
El-Achkar, Tarek M.;McCracken, Ruth;Wu, Xue-Ru
首页--期刊主要分类--期刊细介绍--期刊题录与文摘--期刊详细文摘内容在急性肾损伤的恢复过程中，Tamm-Horsfall蛋白被转移到粗大的升肢、间质和循环的基底外侧区域。Am J Physiol肾脏Physiol 304：F1066-F1075,2013。2013年2月6日首次出版；DOI：10.1152/ajprenal.00543.2012。-Tamm-Horsfall蛋白(THP)是一种糖蛋白，通常针对肾脏粗大的升支(TAL)的顶膜域。我们先前证明，TAL的THP通过两个功能不同的肾小管之间可能的串扰来保护近端小管免受急性肾损伤(AKI)。然而，AKI期间THP移位的范围、时机、特异性和功能效应仍不清楚。利用小鼠脑缺血再灌注(IRI)模型，我们发现TAL中THP的表达在损伤高峰时下调，在IRI后48h显著上调。共聚焦免疫荧光和免疫电子显微镜显示，THP在从TAL的顶膜区恢复到S3节段的基底外侧区、间质和基底室的过程中发生了重大的重定向。这与血清中THP的升高相对应，但与尿液中的THP升高无关。TAL细胞的总体上皮极性没有改变，这是通过正确的顶端靶向Na+-K+-2Cl共转运体(NKCC2)和底侧靶向Na+-K+-ATPase来证明的。与野生型相比，THP-/-小鼠IRI后肾脏恢复明显延迟，可能是由于THP在恢复过程中减少了对促炎症细胞因子和趋化因子如单核细胞趋化蛋白-1的抑制。综上所述，我们的数据表明，THP在AKI后TAL中的重新分布是一种蛋白质特异性事件，其间质的增加负面调节了邻近近端小管中不断演变的炎症信号，从而促进了肾脏的恢复。血清THP升高可作为判断AKI预后的生物标志物。
El-Achkar TM, McCracken R, Liu Y, Heitmeier MR, Bourgeois S, Ryerse J, Wu XR. Tamm-Horsfall protein translocates to the basolateral domain of thick ascending limbs, interstitium, and circulation during recovery from acute kidney injury. Am J Physiol Renal Physiol 304: F1066-F1075, 2013. First published February 6, 2013; doi: 10.1152/ajprenal.00543.2012.-Tamm-Horsfall protein (THP) is a glycoprotein normally targeted to the apical membrane domain of the kidney's thick ascending limbs (TAL). We previously showed that THP of TAL confers protection to proximal tubules against acute kidney injury (AKI) via a possible cross talk between the two functionally distinct tubular segments. However, the extent, timing, specificity, and functional effects of basolateral translocation of THP during AKI remain unclear. Using an ischemia-reperfusion (IRI) model of murine AKI, we show here that, while THP expression in TAL is downregulated at the peak of injury, it is significantly upregulated 48 h after IRI. Confocal immunofluorescence and immunoelectron microscopy reveal a major redirection of THP during recovery from the apical membrane domain of TAL towards the basolateral domain, interstitium, and basal compartment of S3 segments. This corresponds with increased THP in the serum but not in the urine. The overall epithelial polarity of TAL cells does not change, as evidenced by correct apical targeting of Na+-K+-2Cl cotransporter (NKCC2) and basolateral targeting of Na+-K+-ATPase. Compared with the wild-type, THP-/- mice show a significantly delayed renal recovery after IRI, due possibly to reduced suppression by THP of proinflammatory cytokines and chemokines such as monocyte chemoattractant protein-1 during recovery. Taken together, our data suggest that THP redistribution in the TAL after AKI is a protein-specific event and its increased interstitial presence negatively regulates the evolving inflammatory signaling in neighboring proximal tubules, thereby enhancing kidney recovery. The increase of serum THP may be used as a prognostic biomarker for recovery from AKI.