IL-6/Smad2 signaling mediates acute kidney injury and regeneration in a murine model of neonatal hyperoxia
IL-6/Smad2 signaling mediates acute kidney injury and regeneration in a murine model of neonatal hyperoxia
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DOI：
10.1096/fj.201801875rr
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发表时间：
2019-05-01
期刊：
影响因子：
4.8
通讯作者：
Alcazar, Miguel A. Alejandre
中科院分区：
文献类型：
--
作者：
Mohr, Jasmine;Voggel, Jenny;Alcazar, Miguel A. Alejandre
早产与不完全肾发生和慢性肾脏疾病(CKDS)的风险有关。在这种情况下，氧气是拯救生命的，但会导致许多器官的损伤。在这里，我们研究了高氧对肾脏损伤的结构和功能的影响及其对IL-6的依赖。将新生野生型(WT)和IL-6基因敲除(IL-6(-/-))小鼠暴露于85%O2中28d，然后在室内空气中暴露至出生后d(P)70。在整个生命过程中，控制物一直存在于房间空气中。在P28，高氧降低了WT大鼠的肾皮质面积(KCA)；在P70，KCA增大，肾小球数目减少，排钾分数增加，肾小球滤过率略低于对照组。IL-6(-/-)小鼠在高氧后不受这些变化的影响。从机制上讲，WT(-/-)小鼠的急性肾损伤阶段(P28)表现为IL-6(信号转导和转录激活因子3)和转化生长因子-2信号的激活，增加了炎症标志物，扰乱了线粒体的生物发生，减少了肾小管的增殖。在WT小鼠中，P70的再生期以小管增殖为特征，而在IL-6(-/-)小鼠中则不是。这些数据表明，高氧通过一种新的IL-6-Smad2轴增加了CKD的风险。这些途径对药理学方法的适应性可能提供新的途径来保护早产儿免受CKD的影响。Mohr，J.，Vogel，J.，Vohlen，C.，Dinger，K.，Dafinger，C.，Fink，G.，Gobel，H.，Liebau，M.C.，Dotsch，J.，Alejandre Alcazar，M.A.IL-6/Smad2信号调节新生儿高氧小鼠模型的急性肾损伤和再生。
Prematurity is linked to incomplete nephrogenesis and risk of chronic kidney diseases (CKDs). Oxygen is life-saving in that context but induces injury in numerous organs. Here, we studied the structural and functional impact of hyperoxia on renal injury and its IL-6 dependency. Newborn wild-type (WT) and IL-6 knockout (IL-6(-/-)) mice were exposed to 85% O-2 for 28 d, followed by room air until postnatal d (P) 70. Controls were in room air throughout life. At P28, hyperoxia reduced estimated kidney cortex area (KCA) in WT; at P70, KCA was greater, number of glomeruli was fewer, fractional potassium excretion was higher, and glomerular filtration rate was slightly lower than in controls. IL-6(-/-) mice were protected from these changes after hyperoxia. Mechanistically, the acute renal injury phase (P28) showed in WT but not in IL-6(-/-) mice an activation of IL-6 (signal transducer and activator of transcription 3) and TGF- [mothers against decapentaplegic homolog (Smad)2] signaling, increased inflammatory markers, disrupted mitochondrial biogenesis, and reduced tubular proliferation. Regenerative phase at P70 was characterized by tubular proliferation in WT but not in IL-6(-/-) mice. These data demonstrate that hyperoxia increases the risk of CKD through a novel IL-6-Smad2 axis. The amenability of these pathways to pharmacological approaches may offer new avenues to protect premature infants from CKD.Mohr, J., Voggel, J., Vohlen, C., Dinger, K., Dafinger, C., Fink, G., Gobel, H., Liebau, M. C., Dotsch, J., Alejandre Alcazar, M. A. IL-6/Smad2 signaling mediates acute kidney injury and regeneration in a murine model of neonatal hyperoxia.