Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Commun Biol. 2020 Jun 5;3(1):288. doi: 10.1038/s42003-020-1008-z.
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. Jlp deficiency resulted in more severe renal fibrosis in unilateral ureteral obstruction (UUO) mice, while renal fibrosis resistance was observed in TECs-specific transgenic Jlp mice. 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.
肾纤维化受促纤维化和抗纤维化因素的控制。探索抗纤维化因子和机制是预防器官衰竭的一种有吸引力的策略。在这里，我们鉴定出 JNK 相关亮氨酸拉链蛋白 (JLP) 作为一种潜在的内源性抗纤维化因子。JLP 在正常人和小鼠肾脏的肾小管上皮细胞 (TEC) 中主要表达，在纤维化肾脏中下调。Jlp 缺陷导致单侧输尿管梗阻 (UUO) 小鼠更严重的肾纤维化，而 TEC 特异性转基因 Jlp 小鼠则表现出抗纤维化。JLP 通过负调控 TGF-β1 表达和自噬，以及在 TEC 中产生细胞外基质 (ECM)、上皮间质转化 (EMT)、细胞凋亡和细胞周期阻滞的促纤维化作用，发挥其在肾纤维化中的保护作用。我们进一步发现，TGF-β1 和 FGF-2 可以负调控 JLP 的表达。我们的研究表明，JLP 通过与促纤维化因子 TGF-β1 的负相互作用，在肾纤维化中发挥核心作用。
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