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Mycophenolate mofetil reduces renal cortical inducible nitric oxide synthase mRNA expression and diminishes
1Department of Nephrology, Chang Gung Memorial Hospital, 199 Tung-Hwa North Road, Taipei, 105, Taiwan.
Abstract:
Overexpression of inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesis of lupus glomerulonephritis. Mycophenolate mofetil (MMF), a novel immunosuppressive agent, is currently used in organ transplantation and under evaluation for treatment of autoimmune disorders. Mycophenolic acid, the active metabolite of MMF, has been shown to suppress cytokine-induced nitric oxide production in vitro. The aim of this study was to evaluate the effect of MMF on the expression of renal cortical iNOS mRNA and protection against glomerulonephritis in MRL/lpr mice. Three-month-old MRL/lpr mice (n = 6) displaying clinical symptoms of glomerulonephritis were treated for 3 months with MMF (90 mg/kg/day) dissolved in a vehicle. Controls were age- and sex-matched mice (n = 6) that received the vehicle alone. By reverse-transcription competitive polymerase chain reaction, we found that the renal cortical iNOS/beta-actin mRNA ratio was reduced by 30.8% (P <.05) in MMF-treated mice. Furthermore, MMF significantly reduced urinary nitrite production and degree of glomerulosclerosis. The glomerular volume was reduced by 17.5% (P <.001). Proteinuria was also significantly reduced in the MMF-treated group. However, by electrophoretic mobility shift assay, the nuclear binding of nuclear factor-kappaB (NF-kappaB) was not affected by MMF treatment. We conclude that in addition to its immunosuppressive action, MMF may reduce renal cortical iNOS mRNA expression and diminish glomerulosclerosis in MRL/lpr mice independent of modulation of the NF-kappaB pathway.
Insights
Mycophenolate mofetil (MMF) reduces kidney damage in lupus glomerulonephritis mice by lowering inducible nitric oxide synthase (iNOS) mRNA expression. This treatment protected against glomerulosclerosis and proteinuria, independent of nuclear factor-kappaB (NF-kappaB) pathway modulation.
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- Inducible nitric oxide synthase (iNOS) overexpression is linked to lupus glomerulonephritis pathogenesis.
- Mycophenolate mofetil (MMF) is an immunosuppressant evaluated for autoimmune disorders.
- Mycophenolic acid, MMF's active metabolite, inhibits nitric oxide production in vitro.
Purpose of the Study:
- To assess MMF's effect on renal cortical iNOS mRNA expression.
- To evaluate MMF's protective impact against glomerulonephritis in MRL/lpr mice.
Main Methods:
- MRL/lpr mice with glomerulonephritis were treated with MMF (90 mg/kg/day) for 3 months.
- Controls received vehicle alone.
- Renal cortical iNOS mRNA expression was measured using reverse-transcription competitive polymerase chain reaction.
Main Results:
- MMF treatment reduced renal cortical iNOS/beta-actin mRNA ratio by 30.8% (P <.05).
- MMF significantly decreased urinary nitrite, glomerulosclerosis, and glomerular volume (by 17.5%, P <.001).
- Proteinuria was also significantly reduced in MMF-treated mice, while NF-kappaB binding remained unaffected.
Conclusions:
- MMF reduces renal cortical iNOS mRNA expression and glomerulosclerosis in MRL/lpr mice.
- These effects appear independent of modulating the NF-kappaB pathway.
- MMF offers potential therapeutic benefits for lupus glomerulonephritis beyond general immunosuppression.