دورية أكاديمية
Effect of mycophenolate and rapamycin on renal fibrosis in lupus nephritis.
| العنوان: | Effect of mycophenolate and rapamycin on renal fibrosis in lupus nephritis. |
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| المؤلفون: | Zhang C; Department of Medicine, The University of Hong Kong, The University of Hong Kong, Hong Kong., Chan CCY; Department of Medicine, The University of Hong Kong, The University of Hong Kong, Hong Kong., Cheung KF; Department of Medicine, The University of Hong Kong, The University of Hong Kong, Hong Kong., Chau MKM; Department of Medicine, The University of Hong Kong, The University of Hong Kong, Hong Kong., Yap DYH; Department of Medicine, The University of Hong Kong, The University of Hong Kong, Hong Kong., Ma MKM; Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong., Chan KW; Department of Pathology, The University of Hong Kong, Hong Kong., Yung S; Department of Medicine, The University of Hong Kong, The University of Hong Kong, Hong Kong dtmchan@hku.hk ssyyung@hku.hk., Chan TM; Department of Medicine, The University of Hong Kong, The University of Hong Kong, Hong Kong dtmchan@hku.hk ssyyung@hku.hk. |
| المصدر: | Clinical science (London, England : 1979) [Clin Sci (Lond)] 2019 Aug 05; Vol. 133 (15), pp. 1721-1744. Date of Electronic Publication: 2019 Aug 05 (Print Publication: 2019). |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Portland Press on behalf of the Medical Research Society and the Biochemical Society Country of Publication: England NLM ID: 7905731 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1470-8736 (Electronic) Linking ISSN: 01435221 NLM ISO Abbreviation: Clin Sci (Lond) Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: London : Portland Press on behalf of the Medical Research Society and the Biochemical Society Original Publication: London, Medical Research Society. |
| مواضيع طبية MeSH: | Lupus Nephritis/*drug therapy , Mycophenolic Acid/*administration & dosage , Sirolimus/*administration & dosage, Animals ; Chemokine CCL2/genetics ; Chemokine CCL2/metabolism ; Drug Therapy, Combination ; Female ; Fibrosis/drug therapy ; Fibrosis/genetics ; Fibrosis/metabolism ; Fibrosis/pathology ; Humans ; Kidney/drug effects ; Kidney/metabolism ; Kidney/pathology ; Lupus Nephritis/genetics ; Lupus Nephritis/metabolism ; Lupus Nephritis/pathology ; Mice ; Phosphorylation ; Rabbits ; TOR Serine-Threonine Kinases/genetics ; TOR Serine-Threonine Kinases/metabolism ; Transforming Growth Factor beta1/metabolism |
| مستخلص: | Lupus nephritis (LN) leads to chronic kidney disease (CKD) through progressive fibrosis. Mycophenolate inhibits inosine monophosphate dehydrogenase and is a standard treatment for LN. The mammalian or mechanistic target of rapamycin (mTOR) pathway is activated in LN. Rapamycin inhibits mTOR and is effective in preventing kidney transplant rejection, with the additional merits of reduced incidence of malignancies and viral infections. The effect of mycophenolate or rapamycin on kidney fibrosis in LN has not been investigated. We investigated the effects of mycophenolate and rapamycin in New Zealand Black and White first generation (NZB/W F1) murine LN and human mesangial cells (HMCs), focusing on mechanisms leading to kidney fibrosis. Treatment of mice with mycophenolate or rapamycin improved nephritis manifestations, decreased anti-double stranded (ds) DNA antibody titer and reduced immunoglobulin G (IgG) deposition in the kidney. Both mycophenolate and rapamycin, especially the latter, decreased glomerular mTOR Ser 2448 phosphorylation. Renal histology in untreated mice showed mesangial proliferation and progressive glomerulosclerosis with tubular atrophy, and increased expression of transforming growth factor β1 (TGF-β1), monocyte chemoattractant protein-1 (MCP-1), α-smooth muscle actin (α-SMA), fibronectin (FN) and collagen. Both mycophenolate and rapamycin ameliorated the histopathological changes. Results from in vitro experiments showed that both mycophenolate and rapamycin decreased mesangial cell proliferation and their binding with anti-dsDNA antibodies. Mycophenolate and rapamycin also down-regulated mTOR and extracellular signal-regulated kinase (ERK) phosphorylation and inhibited fibrotic responses in mesangial cells that were induced by anti-dsDNA antibodies or TGF-β1. Our findings suggest that, in addition to immunosuppression, mycophenolate and rapamycin may reduce fibrosis in LN, which has important implications in preventing CKD in patients with LN. (© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.) |
| فهرسة مساهمة: | Keywords: Lupus nephritis; fibrosis; mesangial cells; mycophenolate; rapamycin |
| المشرفين على المادة: | 0 (Chemokine CCL2) 0 (Transforming Growth Factor beta1) EC 2.7.11.1 (TOR Serine-Threonine Kinases) HU9DX48N0T (Mycophenolic Acid) W36ZG6FT64 (Sirolimus) |
| تواريخ الأحداث: | Date Created: 20190731 Date Completed: 20200416 Latest Revision: 20211204 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1042/CS20190536 |
| PMID: | 31358596 |
| قاعدة البيانات: | MEDLINE |
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