title: Distinct effects of mycophenolate mofetil and cyclophosphamide on renal fibrosis in NZBWF1/J mice.
abstract: Progression to chronic renal failure varies between patients with lupus nephritis. We compared the effects of mycophenolate mofetil (MMF) and cyclophosphamide (CTX), on renal histology and cellular pathways of fibrosis in murine lupus nephritis. Female NZBWF1/J mice were randomized to treatment with vehicle, methylprednisolone (MP) alone, MMF + MP or CTX + MP for up to 12 weeks, and the effects on clinical parameters, renal histology, and fibrotic processes were investigated. Treatment with MMF + MP or CTX + MP both improved survival, renal function, and decreased anti-dsDNA antibody level and immune complex deposition in kidneys of mice with active nephritis. Vehicle-treated mice showed progressive increase in mesangial proliferation, inflammatory cell infiltration and renal tubular atrophy, associated with PKC-α activation, increased TGF-β1 expression and increased matrix protein deposition. MP treatment alone did not have any significant effect. MMF + MP or CTX + MP treatment for 12 weeks reduced these abnormalities. MMF + MP was more effective than CTX + MP in suppressing fibrotic mediators, histological fibrosis score and expression of TGF-β1, fibronectin and collagen I in the kidney. Results from in vitro experiments on human mesangial cells (HMC) showed that mycophenolic acid (MPA) was more effective than CTX in suppressing PKC-α activation and TGF-β1 secretion induced by human polyclonal anti-dsDNA antibodies. While both MPA and CTX decreased TGF-β1- and TNF-α-induced fibronectin synthesis, only MPA decreased IL-6 induced fibronectin synthesis. MPA and CTX show distinct effects on fibrotic and inflammatory processes in NZBWF1/J murine lupus nephritis, suggesting that MMF + MP may be more effective than CTX + MP in preserving normal renal histology in lupus nephritis.
authors.affiliation: a Department of Medicine , University of Hong Kong , Pokfulam , Hong Kong.
authors.forename: Susan
authors.initials: S
authors.lastname: Yung
authors.affiliation: a Department of Medicine , University of Hong Kong , Pokfulam , Hong Kong.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: a Department of Medicine , University of Hong Kong , Pokfulam , Hong Kong.
authors.forename: Mel K M
authors.initials: MK
authors.lastname: Chau
authors.affiliation: a Department of Medicine , University of Hong Kong , Pokfulam , Hong Kong.
authors.forename: Tak Mao
authors.initials: TM
authors.lastname: Chan
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003520:Cyclophosphamide / Q000494:pharmacology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005353:Fibronectins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D005355:Fibrosis; D005786:Gene Expression Regulation; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D007677:Kidney Function Tests; D008181:Lupus Nephritis / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008775:Methylprednisolone / Q000494:pharmacology; D051379:Mice; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D016019:Survival Analysis; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D000093242:Interleukin-6 Inhibitors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003520:Cyclophosphamide; D005353:Fibronectins; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D008775:Methylprednisolone; D009173:Mycophenolic Acid; D051571:Protein Kinase C-alpha; D053773:Transforming Growth Factor beta1; D000093242:Interleukin-6 Inhibitors; C577686:interleukin-6, mouse
keywords: Cyclophosphamide; lupus nephritis; mesangial cells; methylprednisolone; mycophenolate mofetil; renal fibrosis