TGF-β1-activated kinase-1 regulates inflammation and fibrosis in the obstructed kidney
TGF-β1-activated kinase-1 regulates inflammation and fibrosis in the obstructed kidney
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DOI：
10.1152/ajprenal.00018.2011
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发表时间：
2011-06-01
影响因子：
4.2
通讯作者：
Nikolic-Paterson, David J.
中科院分区：
文献类型：
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作者：
Ma, Frank Y.;Tesch, Greg H.;Nikolic-Paterson, David J.
Ma FY，Tesch GH，Ozols E，Xie M，Schneider MD，Nikolic-Paterson DJ. TGF-β 1激活的激酶-1调节阻塞肾脏的炎症和纤维化。美国肾脏生理学杂志300：F1410-F1421，2011年。首次发表于2011年3月2日; doi：10.1152/ajprenal.00018.2011。c-Jun氨基激酶（JNK）、p38丝裂原活化蛋白激酶（MAPK）和转录因子核因子-κ B（NF-κ B）的激活可驱动肾脏炎症和纤维化。然而，在肾脏疾病中激活这些通路的上游MAP激酶（MAP 3 K）酶是未知的。我们确定了一种候选的MAP 3 K酶，转化生长因子β 1激活的激酶1（TAK 1/MAP 3 K7），在激活JNK，p38，和NF-κ B B在阻塞的肾脏中的作用，在成年小鼠中使用条件性基因缺失，并评估了TAK 1缺失对肾脏病理学的潜在保护作用。在培养的肾小管上皮细胞中TAK 1缺失显著抑制IL-1和TNF-α诱导的JNK、p38和NF-κ B信号传导和促炎反应。Map 3 k7 f/fCre-ERTM小鼠（其中他莫昔芬诱导整体TAK 1缺失）和对照Map 3 k7 f/f小鼠在单侧输尿管梗阻（UUO）时给予他莫昔芬，然后在2、4或5天后处死。他莫昔芬处理的对照组Map 3 k7 f/f小鼠在第2、4和5天显示出JNK、p38和NF-κ B信号传导的预期激活，巨噬细胞浸润和促炎分子（IL-1 α、TNF-α、NOS 2和CCL 2）mRNA水平上调。对照组Map 3 k7 f/f小鼠也显示梗阻肾中的间质肌成纤维细胞积聚和胶原沉积。Map 3 k7 f/fCre-ERTM小鼠的他莫昔芬治疗在第4天引起肾TAK 1表达减少60%，在第5天UUO减少>80%。与TAK 1缺失一致，JNK、p38和NF-κ B信号传导的激活在第4至5天UUO时被显著抑制，这停止了肾巨噬细胞积聚和促炎分子的表达。TAK 1缺失也阻止了肾纤维化在肌成纤维细胞积累、胶原沉积和促纤维化分子表达方面的发展。总之，这些研究确定了TAK 1作为阻塞肾脏中JNK、p38和NF-κ B信号传导的主要上游激活剂，并且它们确定了TAK 1在肾脏炎症和纤维化中的病理作用。
Ma FY, Tesch GH, Ozols E, Xie M, Schneider MD, Nikolic-Paterson DJ. TGF-beta 1-activated kinase-1 regulates inflammation and fibrosis in the obstructed kidney. Am J Physiol Renal Physiol 300: F1410-F1421, 2011. First published March 2, 2011; doi:10.1152/ajprenal.00018.2011.-Activation of c-Jun amino kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and the transcription factor nuclear factor-kappa B (NF-kappa B) drives renal inflammation and fibrosis. However, the upstream MAP kinase kinase kinase (MAP3K) enzyme(s) that activate these pathways in kidney disease are unknown. We determined the role of one candidate MAP3K enzyme, transforming growth factor-beta 1-activated kinase-1 (TAK1/MAP3K7), in activation of JNK, p38, and NF-kappa B in the obstructed kidney using conditional gene deletion in adult mice, and assessed the potential protective effect of TAK1 deletion on renal pathology. TAK1 deletion in cultured tubular epithelial cells substantially inhibited IL-1 and TNF-alpha-induced JNK, p38, and NF-kappa B signaling and the proinflammatory response. Map3k7f/fCre-ERTM mice (in which tamoxifen induces global TAK1 deletion) and control Map3k7f/f mice were given tamoxifen at the time of unilateral ureteric obstruction (UUO) and then killed 2, 4, or 5 days later. Tamoxifen-treated control Map3k7f/f mice showed the expected activation of JNK, p38, and NF-kappa B signaling on days 2, 4, and 5, with macrophage infiltration and upregulation of mRNA levels of proinflammatory molecules (IL-1 alpha, TNF-alpha, NOS2, and CCL2). Control Map3k7f/f mice also showed interstitial myofibroblast accumulation and collagen deposition in the obstructed kidney. Tamoxifen treatment of Map3k7f/fCre-ERTM mice caused a 60% reduction in renal TAK1 expression on day 4 and >80% on day 5 UUO. Coincident with TAK1 deletion, activation of JNK, p38, and NF-kappa B signaling was markedly suppressed on days 4 to 5 UUO, which halted renal macrophage accumulation and expression of proinflammatory molecules. TAK1 deletion also halted the development of renal fibrosis in terms of myofibroblast accumulation, collagen deposition, and expression of profibrotic molecules. In conclusion, these studies establish TAK1 as a major upstream activator of JNK, p38, and NF-kappa B signaling in the obstructed kidney, and they define a pathologic role for TAK1 in renal inflammation and fibrosis.