Lisinopril prevents bullous pemphigoid induced by dipeptidyl peptidase 4 inhibitors via the Mas receptor pathway

Frontiers in Immunology

Immunology

Gen Kayanuma¹  Hiroki Yamamoto¹  Takahide Suzuki¹  Kazuki Nagayasu¹  Hisashi Shirakawa¹  Shuji Kaneko¹  Keisuke Nozawa² 

[1] Department of Molecular Pharmacology, Graduate School and Faculty of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan;Department of Molecular Pharmacology, Graduate School and Faculty of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan;Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan;

关键词: bullous pemphigoid;    dipeptidyl peptidase 4 inhibitor;    lisinopril;    Mas receptor;    FDA Adverse Event Reporting System;    IBM MarketScan Research databases;    macrophage;    matrix metallopeptidase 9;   

DOI  :  10.3389/fimmu.2022.1084960

 received in 2022-10-31, accepted in 2022-12-05,  发布年份 2023

来源: Frontiers

【 摘 要 】

Recent studies have suggested that dipeptidyl peptidase 4 (DPP4) inhibitors increase the risk of development of bullous pemphigoid (BP), which is the most common autoimmune blistering skin disease; however, the associated mechanisms remain unclear, and thus far, no therapeutic targets responsible for drug-induced BP have been identified. Therefore, we used clinical data mining to identify candidate drugs that can suppress DPP4 inhibitor-associated BP, and we experimentally examined the underlying molecular mechanisms using human peripheral blood mononuclear cells (hPBMCs). A search of the US Food and Drug Administration Adverse Event Reporting System and the IBM® MarketScan® Research databases indicated that DPP4 inhibitors increased the risk of BP, and that the concomitant use of lisinopril, an angiotensin-converting enzyme inhibitor, significantly decreased the incidence of BP in patients receiving DPP4 inhibitors. Additionally, in vitro experiments with hPBMCs showed that DPP4 inhibitors upregulated mRNA expression of MMP9 and ACE2, which are responsible for the pathophysiology of BP in monocytes/macrophages. Furthermore, lisinopril and Mas receptor (MasR) inhibitors suppressed DPP4 inhibitor-induced upregulation of MMP9. These findings suggest that the modulation of the renin-angiotensin system, especially the angiotensin1-7/MasR axis, is a therapeutic target in DPP4 inhibitor-associated BP.

【 授权许可】

Unknown   
Copyright © 2023 Nozawa, Suzuki, Kayanuma, Yamamoto, Nagayasu, Shirakawa and Kaneko