ADAMTS13 attenuates renal fibrosis by suppressing thrombospondin 1 mediated TGF-β1/Smad3 activation

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology Pub Date : 2025-02-08 DOI:10.1016/j.taap.2025.117260

Jie Guo , Suhan Zhou , Honghong Wang , Xingyu Qiu , Fang Dong , Shan Jiang , Nan Xu , Yu Cui , Ruisheng Liu , Pengyun Li , Zufu Ma , Liang Zhao , En Yin Lai

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引用次数: 0

Abstract

Renal fibrosis is a common pathologic pathway for the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD). Its mechanisms are unclear and it lacks effective therapy. Thrombospondin 1 (TSP1) mediated transforming growth factor-β1 (TGF-β1) activation was confirmed to promote renal fibrosis. Recently, a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13), was reported to inhibit Thrombospondin 1 (TSP1) mediated Ca²⁺ signaling in the myocardial cell, besides its cleavage of von Willebrand factor (VWF). Therefore, we hypothesized that ADAMTS13 might protect against renal fibrosis by inhibiting TSP1-mediated TGF-β1 activation. In this study, clinical data on renal fibrosis and healthy controls were collected. Renal fibrosis models were established both in vivo and in vitro. In vivo, mice underwent unilateral ureteral obstruction (UUO) for 14 days. In vitro, human proximal tubular epithelial cells (HK−2) were exposed to TGF-β1. The results showed that the expression of ADAMTS13 was decreased accompanied by the increased expression of TSP1 in patients with renal fibrosis and renal fibrosis models in vivo and in vitro. The administration of rhADAMTS13 reduced proteinuria and renal fibrosis in UUO mice. rhADAMTS13 inhibited the expression of TSP1 and the activation of TGF-β1/Smad signaling pathway. The knockdown of ADAMTS13 exhibited a contrary result. The regulation of TSP1 directly affected the protective role of ADAMTS13 in renal fibrosis. Moreover, rhADAMTS13 attenuated inflammation induced by UUO. In conclusion, ADAMTS13 attenuates renal fibrosis induced by UUO. ADAMTS13 exerts its protective role by inhibiting TGF-β1 /Smad signaling via TSP1.

New and noteworthy

ADAMTS13 may be used as a novel molecular marker and a new therapeutic target for renal fibrosis. In this paper, ADAMTS13 was found to have an antifibrotic effect independent of its cleavage of VWF.

查看原文本刊更多论文

ADAMTS13通过抑制血小板反应蛋白1介导的TGF-β1/Smad3激活来减轻肾纤维化

肾纤维化是慢性肾脏疾病（CKD）发展为终末期肾脏疾病（ESRD）的常见病理途径。其机制尚不清楚，缺乏有效的治疗方法。证实血栓反应蛋白1 （TSP1）介导的转化生长因子-β1 （TGF-β1）激活可促进肾纤维化。最近，一种具有血小板反应蛋白1型重复序列的分解素和金属蛋白酶13成员（ADAMTS13）被报道抑制心肌细胞中血小板反应蛋白1 （TSP1）介导的Ca2+信号，除了其对血管性血友病因子（VWF）的裂解。因此，我们假设ADAMTS13可能通过抑制tsp1介导的TGF-β1激活来预防肾纤维化。本研究收集了肾纤维化患者和健康对照者的临床资料。在体内和体外建立肾纤维化模型。在体内，小鼠遭受单侧输尿管梗阻（UUO） 14天。在体外，人近端小管上皮细胞（HK−2）暴露于TGF-β1。结果显示，在体内和体外肾纤维化患者及肾纤维化模型中，ADAMTS13表达降低，TSP1表达升高。给药rhADAMTS13可减少UUO小鼠的蛋白尿和肾纤维化。rhADAMTS13抑制TSP1的表达，激活TGF-β1/Smad信号通路。而敲低ADAMTS13则表现出相反的结果。TSP1的调控直接影响ADAMTS13在肾纤维化中的保护作用。此外，rhADAMTS13可以减轻UUO引起的炎症。综上所述，ADAMTS13可减轻UUO引起的肾纤维化。ADAMTS13通过TSP1抑制TGF-β1 /Smad信号通路发挥保护作用。新的值得注意的是，adamts13可能作为一种新的分子标记物和治疗肾纤维化的新靶点。本文发现ADAMTS13具有独立于VWF切割的抗纤维化作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.