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.

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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.