File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
Supplementary

Article: Effect of Mycophenolate and Rapamycin on Renal Fibrosis in Lupus Nephritis

TitleEffect of Mycophenolate and Rapamycin on Renal Fibrosis in Lupus Nephritis
Authors
Issue Date2019
PublisherPortland Press Ltd. The Journal's web site is located at http://www.clinsci.org/
Citation
Clinical Science, 2019, v. 133 n. 15, p. 1721-1744 How to Cite?
AbstractLupus 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 Ser2448 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).
Persistent Identifierhttp://hdl.handle.net/10722/273928
ISSN
2019 Impact Factor: 5.223
2015 SCImago Journal Rankings: 2.427
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorZhang, C-
dc.contributor.authorChan, CYC-
dc.contributor.authorCheung, KF-
dc.contributor.authorChau, KM-
dc.contributor.authorYap, YHD-
dc.contributor.authorMa, MK-
dc.contributor.authorChan, KW-
dc.contributor.authorYung, SSY-
dc.contributor.authorChan, DTM-
dc.date.accessioned2019-08-18T14:51:31Z-
dc.date.available2019-08-18T14:51:31Z-
dc.date.issued2019-
dc.identifier.citationClinical Science, 2019, v. 133 n. 15, p. 1721-1744-
dc.identifier.issn0143-5221-
dc.identifier.urihttp://hdl.handle.net/10722/273928-
dc.description.abstractLupus 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 Ser2448 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).-
dc.languageeng-
dc.publisherPortland Press Ltd. The Journal's web site is located at http://www.clinsci.org/-
dc.relation.ispartofClinical Science-
dc.rightsThe final version of record is available at [Journal URL].-
dc.titleEffect of Mycophenolate and Rapamycin on Renal Fibrosis in Lupus Nephritis-
dc.typeArticle-
dc.identifier.emailChan, CYC: calebccy@hku.hk-
dc.identifier.emailYap, YHD: desmondy@hku.hk-
dc.identifier.emailChan, KW: kwchan@pathology.hku.hk-
dc.identifier.emailYung, SSY: ssyyung@hku.hk-
dc.identifier.emailChan, DTM: dtmchan@hkucc.hku.hk-
dc.identifier.authorityYap, YHD=rp01607-
dc.identifier.authorityChan, KW=rp00330-
dc.identifier.authorityYung, SSY=rp00455-
dc.identifier.authorityChan, DTM=rp00394-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1042/CS20190536-
dc.identifier.pmid31358596-
dc.identifier.scopuseid_2-s2.0-85071070229-
dc.identifier.hkuros301150-
dc.identifier.volume133-
dc.identifier.issue15-
dc.identifier.spage1721-
dc.identifier.epage1744-
dc.identifier.isiWOS:000482101500002-
dc.publisher.placeUnited Kingdom-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats