Development of a novel Poly (I:C)-induced murine model with accelerated lupus nephritis and examination of the therapeutic effects of mycophenolate mofetil and a cathepsin S inhibitor
Copyright © 2022 Elsevier B.V. All rights reserved..
Systemic lupus erythematosus (SLE) is an autoimmune disease involving multi-organ systems with a widely heterogeneous clinical presentation. Renal involvement, observed mainly in lupus nephritis (LN), is the most common organ lesion associated with SLE and a determinant of prognosis. However, treatment of LN remains controversial and challenging, prompting the need for novel therapeutic approaches. In particular, development of a clinically relevant LN animal model would greatly facilitate the development of new treatments. Here, we report a novel murine model for LN established by administering polyinosinic-polycytidylic acid (Poly (I:C)) to NZB/W F1 mice. We investigated the effectiveness of administering Poly (I:C) to NZB/W F1 mice for accelerating nephritis onset and explored the optimal conditions under which to enroll mice with nephritis with similar pathology for studying treatment candidates. Gene-expression analysis revealed that activation of macrophages, which are reported to be involved in the progression of LN in patients, was a unique characteristic in this accelerated nephritis model. Evaluation of the therapeutic effect of mycophenolate mofetil (MMF), a recommended first-choice agent for LN, in this novel LN model showed that MMF significantly reduced proteinuria. The cathepsin S (CatS) inhibitor ASP1617, which has been reported to prevent development of lupus-like glomerulonephritis in the spontaneous NZB/W F1 mouse model, also showed marked therapeutic effect in this model. Our novel Poly (I:C) accelerated LN model would thus be very useful for screening clinical candidates for LN, and CatS may be an attractive therapeutic target for the treatment of LN.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:938 |
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| Enthalten in: |
European journal of pharmacology - 938(2023) vom: 05. Jan., Seite 175440 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kawato, Yuka [VerfasserIn] |
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| Links: |
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| Themen: |
Cathepsin S |
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| Anmerkungen: |
Date Completed 19.12.2022 Date Revised 21.12.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejphar.2022.175440 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM349764751 |
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| 245 | 1 | 0 | |a Development of a novel Poly (I:C)-induced murine model with accelerated lupus nephritis and examination of the therapeutic effects of mycophenolate mofetil and a cathepsin S inhibitor |
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| 520 | |a Systemic lupus erythematosus (SLE) is an autoimmune disease involving multi-organ systems with a widely heterogeneous clinical presentation. Renal involvement, observed mainly in lupus nephritis (LN), is the most common organ lesion associated with SLE and a determinant of prognosis. However, treatment of LN remains controversial and challenging, prompting the need for novel therapeutic approaches. In particular, development of a clinically relevant LN animal model would greatly facilitate the development of new treatments. Here, we report a novel murine model for LN established by administering polyinosinic-polycytidylic acid (Poly (I:C)) to NZB/W F1 mice. We investigated the effectiveness of administering Poly (I:C) to NZB/W F1 mice for accelerating nephritis onset and explored the optimal conditions under which to enroll mice with nephritis with similar pathology for studying treatment candidates. Gene-expression analysis revealed that activation of macrophages, which are reported to be involved in the progression of LN in patients, was a unique characteristic in this accelerated nephritis model. Evaluation of the therapeutic effect of mycophenolate mofetil (MMF), a recommended first-choice agent for LN, in this novel LN model showed that MMF significantly reduced proteinuria. The cathepsin S (CatS) inhibitor ASP1617, which has been reported to prevent development of lupus-like glomerulonephritis in the spontaneous NZB/W F1 mouse model, also showed marked therapeutic effect in this model. Our novel Poly (I:C) accelerated LN model would thus be very useful for screening clinical candidates for LN, and CatS may be an attractive therapeutic target for the treatment of LN | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Cathepsin S | |
| 650 | 4 | |a Lupus nephritis | |
| 650 | 4 | |a Mycophenolate mofetil | |
| 650 | 4 | |a NZB/W F1 mice | |
| 650 | 4 | |a Polyinosinic-polycytidylic acid | |
| 650 | 7 | |a Mycophenolic Acid |2 NLM | |
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| 650 | 7 | |a cathepsin S |2 NLM | |
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| 650 | 7 | |a Poly I-C |2 NLM | |
| 650 | 7 | |a O84C90HH2L |2 NLM | |
| 650 | 7 | |a Immunosuppressive Agents |2 NLM | |
| 700 | 1 | |a Fukahori, Hidehiko |e verfasserin |4 aut | |
| 700 | 1 | |a Nakamura, Koji |e verfasserin |4 aut | |
| 700 | 1 | |a Kubo, Kaori |e verfasserin |4 aut | |
| 700 | 1 | |a Hiramitsu, Masaki |e verfasserin |4 aut | |
| 700 | 1 | |a Kinugasa, Fumitaka |e verfasserin |4 aut | |
| 700 | 1 | |a Morokata, Tatsuaki |e verfasserin |4 aut | |
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