Effect of mycophenolate mofetil on severity of nephritis and nitric oxide production in lupus-prone MRL/lpr mice.
Mycophenolate mofetil (MMF), an immunosuppressive drug commonly used in organ transplantation, is increasingly being used to treat autoimmune diseases including systemic lupus erythematosus (SLE). Excessive production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesis of lupus nephritis. We evaluated the effect of MMF on the severity of nephritis and the production of NO in lupus-prone MRL/lpr mice. Eight-week-old female MRL/lpr mice (n = 20) were treated with MMF (100 mg/kg/day) by oral gavage for 12 weeks. Control mice (n = 20) received vehicle on the same schedule. The mice were killed after 12 weeks of treatment. Treatment with MMF significantly decreased the amount of proteinuria, prolonged survival and reduced the histological severity of glomerulonephritis. Urinary nitrite/nitrate excretion in the MMF-treated mice was significantly reduced during the first 8 weeks of treatment. However, by the end of the 12 weeks' treatment period, there was no significant difference between vehicle and MMF-treated mice in terms of urinary nitrite/nitrate excretion, intra-renal production of NO, expression of iNOS protein and induction of iNOS mRNA. We conclude that MMF is effective in attenuating the severity of nephritis in MRL/lpr mice. The beneficial effects of MMF on lupus nephritis during the early phase of the disease might be partly attributed to the inhibition of NO production. The inhibitory effect of MMF on NO production diminishes as the disease progresses. MMF probably has additional, as yet undefined mode of actions to fully account for its beneficial effects on lupus nephritis.
Lui
S L
SL
Division of Nephrology, University Department of Medicine, Queen Mary Hospital, Hong Kong, Republic of China. sllui@hkucc.hku.hk
Tsang
R
R
Wong
D
D
Chan
K W
KW
Chan
T M
TM
Fung
P C W
PC
Lai
K N
KN
D000818:Animals; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000201:enzymology; D008181:Lupus Nephritis / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality; D051379:Mice; D019463:Mice, Inbred MRL lpr; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000652:urine; D011507:Proteinuria / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D012333:RNA, Messenger / Q000032:analysis; D012720:Severity of Illness Index; D015996:Survival Rate
D007166:Immunosuppressive Agents; D009566:Nitrates; D009573:Nitrites; D012333:RNA, Messenger; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D009173:Mycophenolic Acid