YAP promotes AP-1 expression in tubular epithelial cells in the kidney.

IF 3.7 2区 医学 Q1 PHYSIOLOGY American Journal of Physiology-renal Physiology Pub Date : 2023-06-01 DOI:10.1152/ajprenal.00246.2022
Yang Liu, Chunhua Xu, Jinhong Li, Yu Zhang, Xiaohua Wang, Yang Wang, Jinzhong Qin, Zhihua Zheng, Yin Xia
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引用次数: 1

Abstract

Chronic kidney disease (CKD) is a major health problem. Kidney fibrosis is a hallmark and final common pathway of CKD. The Hippo/yes-associated protein (YAP) pathway regulates organ size, inflammation, and tumorigenesis. Our previous study demonstrated tubular YAP activation by tubule-specific double knockout of mammalian STE20-like protein kinase 1/2 (Mst1/2) induced CKD in mice, but the underlying mechanisms remain to be fully elucidated. Activator protein (AP)-1 activation was found to promote tubular atrophy and tubulointerstitial fibrosis. Therefore, we studied whether YAP regulates AP-1 expression in the kidney. We found that expression of various AP-1 components was induced in kidneys subjected to unilateral ureteric obstruction and in Mst1/2 double knockout kidneys, and these inductions were blocked by deletion of Yap in tubular cells, with Fosl1 being most affected compared with other AP-1 genes. Inhibition of Yap also most highly suppressed Fosl1 expression among AP-1 genes in HK-2 and IMCD3 renal tubular cells. YAP bound to the Fosl1 promoter and promoted Fosl1 promoter-luciferase activity. Our results suggest that YAP controls AP-1 expression and that Fosl1 is the primary target of YAP in renal tubular cells.NEW & NOTEWORTHY Yes-associated protein (YAP) activation leads to tubular injury, renal inflammation, and fibrosis, but the underlying mechanisms are not fully understood. We now provide genetic evidence that YAP promotes activator protein-1 expression and that Fosl1 is the primary target of YAP in renal tubular cells.

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YAP促进肾小管上皮细胞AP-1的表达。
慢性肾脏疾病(CKD)是一个主要的健康问题。肾纤维化是CKD的标志和最终共同途径。Hippo/yes相关蛋白(YAP)通路调节器官大小、炎症和肿瘤发生。我们之前的研究表明,通过小管特异性双敲除哺乳动物ste20样蛋白激酶1/2 (Mst1/2),可以激活小管YAP,从而诱导小鼠CKD,但其潜在机制仍有待充分阐明。激活蛋白(AP)-1激活可促进小管萎缩和小管间质纤维化。因此,我们研究YAP是否调节肾脏AP-1的表达。我们发现,在单侧输尿管梗阻的肾脏和Mst1/2双敲除的肾脏中,各种AP-1成分的表达被诱导,这些诱导被小管细胞中Yap的缺失所阻断,与其他AP-1基因相比,Fosl1受到的影响最大。Yap的抑制也高度抑制了HK-2和IMCD3肾小管细胞AP-1基因中Fosl1的表达。YAP与Fosl1启动子结合,促进Fosl1启动子-荧光素酶活性。我们的研究结果表明,YAP控制AP-1的表达,Fosl1是YAP在肾小管细胞中的主要靶点。yes相关蛋白(YAP)激活可导致肾小管损伤、肾脏炎症和纤维化,但其潜在机制尚不完全清楚。我们现在提供的遗传证据表明,YAP促进激活蛋白1的表达,并且Fosl1是YAP在肾小管细胞中的主要靶点。
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来源期刊
CiteScore
8.40
自引率
7.10%
发文量
154
审稿时长
2-4 weeks
期刊介绍: The American Journal of Physiology - Renal Physiology publishes original manuscripts on timely topics in both basic science and clinical research. Published articles address a broad range of subjects relating to the kidney and urinary tract, and may involve human or animal models, individual cell types, and isolated membrane systems. Also covered are the pathophysiological basis of renal disease processes, regulation of body fluids, and clinical research that provides mechanistic insights. Studies of renal function may be conducted using a wide range of approaches, such as biochemistry, immunology, genetics, mathematical modeling, molecular biology, as well as physiological and clinical methodologies.
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