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

Nozawa, Keisuke; Suzuki, Takahide; Kayanuma, Gen; Yamamoto, Hiroki; Nagayasu, Kazuki; Shirakawa, Hisashi; Kaneko, Shuji

doi:10.3389/fimmu.2022.1084960

Cited by 6 publications

(5 citation statements)

References 47 publications

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“…Lisinopril, identified through analysis of clinical data as a potential ACEI for the treatment of BP, was found to reduce the expression of MMP9 mRNA and the polarization of M2 macrophages induced by DPP4Is. These results provide valuable insights into the underlying mechanisms of BP and emphasize a promising target for the treatment [125].…”

Section: Bullous Pemphigoid (Bp)mentioning

confidence: 76%

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The Renin-Angiotensin System: The Challenge behind Autoimmune Dermatological Diseases

Maranduca,

Cosovanu,

Clim

et al. 2023

Diagnostics

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Autoimmune dermatological diseases (AIDD) encompass a diverse group of disorders characterized by aberrant immune responses targeting the skin and its associated structures. In recent years, emerging evidence suggests a potential involvement of the renin–angiotensin system (RAS) in the pathogenesis and progression of these conditions. RAS is a multicomponent cascade, primarily known for its role in regulating blood pressure and fluid balance. All of the RAS components play an important role in controlling inflammation and other immune responses. Angiotensin II, the main effector, acts on two essential receptors: Angiotensin Receptor 1 and 2 (AT1R and AT2R). A disturbance in the axis can lead to many pathological processes, including autoimmune (AI) diseases. AT1R activation triggers diverse signaling cascades involved in inflammation, fibrosis and tissue remodeling. Experimental studies have demonstrated the presence of AT1R in various cutaneous cells and immune cells, further emphasizing its potential contribution to the AI processes in the skin. Furthermore, recent investigations have highlighted the role of other RAS components, beyond angiotensin-converting enzyme (ACE) and Ang II, that may contribute to the pathophysiology of AIDD. Alternative pathways involving ACE2, Ang receptors and Ang-(1-7) have been implicated in regulating immune responses and tissue homeostasis within the skin microenvironment. Understanding the intricate involvement of the RAS in AIDD may provide novel therapeutic opportunities. Targeting specific components of the RAS, such as angiotensin receptor blockers (ARBs), ACE inhibitors (ACEIs) or alternative RAS pathway modulators, could potentially ameliorate inflammatory responses, reduce tissue damage and lessen disease manifestations. Further research is warranted to outline the exact mechanisms underlying RAS-mediated immune dysregulation in AIDD. This abstract aims to provide a concise overview of the intricate interplay between the RAS and AIDD. Therefore, we elaborate a systematic review of the potential challenge of RAS in the AIDD, including psoriasis, systemic sclerosis, vitiligo, lupus erythematosus and many more.

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Section: Bullous Pemphigoid (Bp)mentioning

confidence: 76%

“…Intriguing, Nozawa et al [125] conducted the first study to reveal that lisinopril can prevent the development of dipeptidyl peptidase 4 inhibitor (DPP4I)-associated BP. DPP4Is are oral antidiabetic drugs used in the treatment of type two diabetes mellitus, but they increase the risk of BP, through unclear mechanisms.…”

Section: Bullous Pemphigoid (Bp)mentioning

confidence: 99%

The Renin-Angiotensin System: The Challenge behind Autoimmune Dermatological Diseases

Maranduca,

Cosovanu,

Clim

et al. 2023

Diagnostics

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“…Lisinopril and MasR inhibitors effectively suppress the DPP4i-induced upregulation of MMP9, suggesting that the modulation of the renin-angiotensin system could stand as a therapeutic approach for DPP4i-BP. This intriguing in vitro finding is sustained by research databases, which indicate that the concomitant use of lisinopril in patients taking DPP4i can significantly reduce the incidence of DPP4i-BP [109].…”

Section: Currently Described Immune and Pathogenic Mechanismsmentioning

confidence: 88%

“…Specifically, captopril contains a thiol group within its molecular structure, so it can directly interact with sulfhydryl groups in the BMZ [172]. These proposed pathogenic mechanisms contrast with in vitro and population-based studies that show the decreased incidence of DPP4i-BP when lisinopril is used concomitantly with DPP4i [109].…”

Section: Bullous Pemphigoid Associated With Cardiovascular Drugsmentioning

confidence: 97%

From Molecular Insights to Clinical Perspectives in Drug-Associated Bullous Pemphigoid

de Nicolas-Ruanes,

Ballester-Martinez,

Garcia-Mouronte

et al. 2023

IJMS

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Bullous pemphigoid (BP), the most common autoimmune blistering disease, is characterized by the presence of autoantibodies targeting BP180 and BP230 in the basement membrane zone. This leads to the activation of complement-dependent and independent pathways, resulting in proteolytic cleavage at the dermoepidermal junction and an eosinophilic inflammatory response. While numerous drugs have been associated with BP in the literature, causality and pathogenic mechanisms remain elusive in most cases. Dipeptidyl peptidase 4 inhibitors (DPP4i), in particular, are the most frequently reported drugs related to BP and, therefore, have been extensively investigated. They can potentially trigger BP through the impaired proteolytic degradation of BP180, combined with immune dysregulation. DPP4i-associated BP can be categorized into true drug-induced BP and drug-triggered BP, with the latter resembling classic BP. Antineoplastic immunotherapy is increasingly associated with BP, with both B and T cells involved. Other drugs, including biologics, diuretics and cardiovascular and neuropsychiatric agents, present weaker evidence and poorly understood pathogenic mechanisms. Further research is needed due to the growing incidence of BP and the increasing identification of new potential triggers.

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“…Our findings provide new insights into the pathophysiology of BP and highlight novel drug targets for treating BP. 5)…”

Section: Biographymentioning

confidence: 99%

A Novel Strategy for the Discovery of Drug Targets: Integrating Clinical Evidence with Molecular Studies

Kaneko

2024

Biological & Pharmaceutical Bulletin

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The mechanisms of several drugs remain unclear, limiting our understanding of how they exert their effects. Receptor affinities have not been comprehensively measured during drug development, and the safety investigations in humans are limited. Therefore, numerous unknown adverse and beneficial effects of drugs in humans persist. In this review, I highlight our achievements in identifying the unexpected beneficial effects of drugs through the analysis of real-world clinical data, which can contribute to drug repositioning and target finding. (1) Through the analysis of real-world data, we found that the anti-arrhythmic amiodarone induced interstitial lung disease, leading to fibrosis. Surprisingly, concurrent use of an anti-thrombin drug, dabigatran mitigated these adverse events. Pharmacological studies using animal models have mimicked this phenomenon and revealed the molecular mechanisms associated with the platelet-derived growth factoralpha receptors. (2) The antidiabetic dipeptidyl-peptidase 4 inhibitors increased the risk of an autoimmune disease, bullous pemphigoid, which was reduced by the concomitant use of lisinopril. Pharmacological studies using human peripheral blood mononuclear cells have revealed that lisinopril suppressed the skin disorders by inhibiting the expression of cutaneous matrix metalloproteinase 9 in macrophages. (3) The antimicrobial fluoroquinolones increased the risk of tendinopathy, which was reduced by the concomitant use of dexamethasone. However, clinical guidelines have suggested that corticosteroid increases the risk of tendinopathy. Our investigation demonstrated that fluoroquinolones impaired tendon cells through DNA damage by generating reactive oxygen species. In contrast, dexamethasone exhibited an acute beneficial effect on tendon tissue by upregulating the expression of a radical scavenger, glutathione peroxidase 3.

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

Cited by 6 publications

References 47 publications

The Renin-Angiotensin System: The Challenge behind Autoimmune Dermatological Diseases

The Renin-Angiotensin System: The Challenge behind Autoimmune Dermatological Diseases

From Molecular Insights to Clinical Perspectives in Drug-Associated Bullous Pemphigoid

A Novel Strategy for the Discovery of Drug Targets: Integrating Clinical Evidence with Molecular Studies

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