A negative feedback loop between JNK-associated leucine zipper protein and TGF-beta 1 regulates kidney fibrosis
A negative feedback loop between JNK-associated leucine zipper protein and TGF-beta 1 regulates kidney fibrosis
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JNK 相关亮氨酸拉链蛋白和 TGF-β1 之间的负反馈环调节肾纤维化
DOI：
10.1038/s42003-020-1008-z
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发表时间：
2020
影响因子：
5.9
通讯作者：
Wang Huiming
中科院分区：
文献类型：
--
作者：
Yan Qi;Zhu Kai;Zhang Lu;Fu Qiang;Chen Zhaowei;Liu Shan;Fu Dou;Nakazato Ryota;Yoshioka Katsuji;Diao Bo;Ding Guohua;Li Xiaogang;Wang Huiming
肾纤维化受促纤维化和抗纤维化力量控制。探索抗纤维化因子和机制是预防器官衰竭的有吸引力的策略。在这里，我们确定JNK相关的亮氨酸拉链蛋白（JLP）作为一个潜在的内源性抗纤维化因子。JLP主要表达于正常人或小鼠肾脏的肾小管上皮细胞（TECs），在纤维化肾脏中表达下调，JLP缺陷导致单侧输尿管梗阻（UUO）小鼠更严重的肾纤维化，而在TECs特异性转基因JLP小鼠中观察到肾纤维化抵抗。JLP通过负性调节TGF-β1的表达和自噬，以及ECM的产生、上皮细胞向间质细胞转化（EMT）、凋亡和细胞周期阻滞的促纤维化作用来执行其在肾纤维化中的保护作用。TGF-β1和FGF-2对JLP的表达有负调节作用。我们的研究表明，JLP通过其与促纤维化因子TGF-β1的负性串扰在肾纤维化中发挥核心作用。
Renal fibrosis is controlled by profibrotic and antifibrotic forces. Exploring anti-fibrosis factors and mechanisms is an attractive strategy to prevent organ failure. Here we identified the JNK-associated leucine zipper protein (JLP) as a potential endogenous antifibrotic factor. JLP, predominantly expressed in renal tubular epithelial cells (TECs) in normal human or mouse kidneys, was downregulated in fibrotic kidneys.Jlpdeficiency resulted in more severe renal fibrosis in unilateral ureteral obstruction (UUO) mice, while renal fibrosis resistance was observed in TECs-specific transgenicJlpmice. JLP executes its protective role in renal fibrosis via negatively regulating TGF-β1 expression and autophagy, and the profibrotic effects of ECM production, epithelial-to-mesenchymal transition (EMT), apoptosis and cell cycle arrest in TECs. We further found that TGF-β1 and FGF-2 could negatively regulate the expression of JLP. Our study suggests that JLP plays a central role in renal fibrosis via its negative crosstalk with the profibrotic factor, TGF-β1.