CP-25 enhances OAT1-mediated absorption of methotrexate in synoviocytes of collagen-induced arthritis rats  

作　　者：Chun Wang Hao Tang Yong Wang Yan Chang Yi-jin Wu Bin Wang Wei Sun Feng Xiao Wei Wei 

机构地区：[1]Institute of Clinical Pharmacology,Anhui Medical University,Key Laboratory of Anti-Inflammatory and Immune Medicine,Ministry of Education,Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine,Hefei,230032,China

出　　处：《Acta Pharmacologica Sinica》2023年第1期81-91,共11页中国药理学报（英文版）

基　　金：This work was financially supported by the National Natural Science Foundation of China (grant number 81973332);the Anhui Provincial Natural Science Foundation (grant number 2008085QH402);the Scientific Research Foundation of the Institute for Translational Medicine of Anhui Province (grant number 2017zhyx33);the Enhancement Programme for Basic and Clinical Cooperative Research of Anhui Medical University (grant number 2019xkjT016);the Key Projects of Anhui Province University Outstanding Youth Talent Support Programme (grant number gxyqZD2019017).

摘　　要：Organic anion transporter 1 (OAT1) plays a major role in mediating the absorption, distribution and excretion of drugs and other xenobiotics in the human body. In this study we explored the OAT1 status in rheumatoid arthritis (RA) patients and arthritic animals and its role in regulating the anti-arthritic activity of methotrexate (MTX). We showed that OAT1 expression was significantly downregulated in synovial tissues from RA patients compared with that in the control patients. In collagen-induced arthritis (CIA) rats, synovial OAT1 expression was significantly decreased compared with the control rats. In synoviocytes isolated from CIA rats, PGE2 (0.003–1.75 μM) dose-dependently downregulated OAT1 expression, resulting in decreased absorption of MTX. Silencing OAT1 in synoviocytes caused a 43.7% reduction in the uptake of MTX. Furthermore, knockdown of OAT1 impaired MTX-induced inhibitory effects on the viability and migration of synoviocytes isolated from CIA rats. Moreover, injection of OAT1-shRNA into articular cavity of CIA rats significantly decreased synovial OAT1 expression and impaired the anti-arthritic action of MTX, while injection of lentivirus containing OAT1 sequences led to the opposite results. Interestingly, we found that paeoniflorin-6’-O-benzene sulfonate (CP-25) upregulated OAT1 expression both in vitro and in vivo and promoted MTX uptake by synoviocytes via regulating OAT1 expression and function. Taken together, OAT1 plays a major role in regulating MTX uptake by synoviocytes and the anti-arthritic activity of MTX. OAT1 is downregulated in RA and CIA rats, which can be improved by CP-25.

关 键 词：rheumatoid arthritis SYNOVIOCYTE organic anion transporter 1 METHOTREXATE C-25 drug absorption collagen-induced arthritis(CIA)model 

分 类 号：R73[医药卫生—肿瘤]