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Effect of Mycophenolate and Rapamycin on Renal Fibrosis in Lupus Nephritis.

Authors
  • Zhang, Chenzhu1
  • Chan, Caleb Cy1
  • Cheung, Kwok Fan1
  • Chau, Mel Km1
  • Yap, Desmond Yh1
  • Ma, Maggie Km1
  • Chan, Kwok Wah1
  • Yung, Susan1
  • Chan, Tak Mao2
  • 1 The University of Hong Kong, Hong Kong, Hong Kong. , (Hong Kong SAR China)
  • 2 The University of Hong Kong, Hong Kong, Hong Kong [email protected] , (Hong Kong SAR China)
Type
Published Article
Journal
Clinical Science
Publisher
Portland Press
Publication Date
Jul 29, 2019
Identifiers
DOI: 10.1042/CS20190536
PMID: 31358596
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Lupus nephritis (LN) leads to chronic kidney disease 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 NZB/W F1 murine LN and human mesangial cells (HMC), focusing on mechanisms leading to kidney fibrosis. Treatment of mice with mycophenolate or rapamycin improved nephritis manifestations, decreased anti-double stranded (ds)DNA antibody titre, and reduced IgG deposition in the kidney. Both mycophenolate and rapamycin, especially the latter, decreased glomerular mTOR Ser2448 phosphorylation. Renal histology in untreated mice showed mesangial proliferation and progressive glomerulosclerosis with tubular atrophy, and increased expression of TGF-β1, MCP-1, α-smooth muscle actin, fibronectin 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 by anti-dsDNA antibodies. Mycophenolate and rapamycin also down-regulated mTOR and extracellular signal-regulated kinase 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 chronic kidney disease in patients with LN. ©2019 The Author(s).

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