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Effect of mycophenolate mofetil on glomerulosclerosis and renal oxidative stress in rats
Christiane Van den Branden1, Bart Ceyssens, Marina Pauwels
1Department of Human Anatomy, Vrije Universiteit Brussel, Brussels, Belgium. cvdbrand@vub.ac.be
Background/Aims:
Mycophenolate mofetil (MMF) is known to attenuate glomerulosclerosis in experimental models of renal failure. We investigated whether this is mediated by reduction of oxidative stress.
Methods:
Effects of MMF on oxidative stress are studied in an experimental rat model (NA model) involving unilateral nephrectomy and two intravenous injections with adriamycin (2 mg/kg). Rats are sacrificed after 2 and 6 weeks. Glomerulosclerosis and tubulointerstitial lesions are demonstrated by histological techniques. Presence of macrophages/monocytes (ED1) and myofibroblasts (alpha-SMA) is demonstrated by immunohistochemistry. Oxidative stress is evaluated by enzymatic measurements (AOE), spectrofluorometry (TBARS), immunohistochemistry (MDA and HNE) and histology (ferric iron deposition).
Results:
The NA model shows proteinuria, hypercholesterolemia, beginning glomerulosclerosis, tubulointerstitial sclerosis and tubular dilatation, glomerular, periglomerular and interstitial presence of alpha-SMA and increased presence of macrophages/monocytes after 6 weeks. Oxidative stress in renal cortex is apparent (increased cortex TBARS concentration, increased glomerular presence of MDA and HNE, decreased activity of antioxidant enzymes, ferric iron deposition in proximal tubules) after 6 weeks. MMF administration results in a decrease of glomerulosclerosis, interstitial sclerosis, glomerular and periglomerular expression of alpha-SMA and the number of ED1-positive cells in tubulointerstitium and glomeruli. Proteinuria and cholesterolemia are not decreased. TBARS level, and activities of catalase, Mn and Cu/Zn superoxide dismutase as well as the presence of ferric iron in the proximal tubules are not changed by MMF treatment. Cortex activity of glutathione peroxidase returns to normal.
Conclusion:
MMF has a favorable effect on glomerular and interstitial fibrosis in the NA model of kidney disease, but not on proteinuria and cholesterolemia. Improvement of fibrosis cannot be explained by major changes in oxidative stress or antioxidant defense.
Insights
Mycophenolate mofetil (MMF) reduces kidney fibrosis in a rat model, but does not improve proteinuria or cholesterolemia. The antifibrotic effect of MMF is not linked to significant changes in oxidative stress markers.
Area of Science:
- Nephrology
- Pharmacology
- Pathology
Background:
- Mycophenolate mofetil (MMF) is recognized for its potential to reduce glomerulosclerosis in experimental renal failure.
- The precise mechanisms underlying MMF's renoprotective effects, particularly concerning oxidative stress, require further elucidation.
Purpose of the Study:
- To investigate whether the antifibrotic effects of Mycophenolate mofetil (MMF) in a rat model of kidney disease are mediated by a reduction in oxidative stress.
- To assess the impact of MMF on markers of fibrosis, inflammation, and oxidative stress in the unilateral nephrectomy and adriamycin-induced (NA) rat model.
Main Methods:
- An experimental rat model (NA model) was established using unilateral nephrectomy and adriamycin injections.
- Histological techniques, immunohistochemistry (for ED1 and alpha-SMA), and biochemical assays (AOE, TBARS, MDA, HNE, ferric iron deposition) were employed to evaluate renal damage, inflammation, and oxidative stress.
- Rats were analyzed at 2 and 6 weeks post-treatment with or without MMF.
Main Results:
- The NA model exhibited significant glomerulosclerosis, tubulointerstitial fibrosis, and increased macrophage infiltration by week 6.
- MMF treatment reduced glomerulosclerosis, interstitial fibrosis, alpha-SMA expression, and macrophage markers.
- MMF did not significantly alter proteinuria, hypercholesterolemia, TBARS levels, or most antioxidant enzyme activities, though glutathione peroxidase activity normalized.
Conclusions:
- Mycophenolate mofetil (MMF) demonstrates antifibrotic efficacy in the NA rat model of kidney disease, improving glomerular and interstitial fibrosis.
- The renoprotective effects of MMF in this model are not attributable to significant reductions in overall oxidative stress or major alterations in antioxidant defense mechanisms.
- MMF's impact on proteinuria and hypercholesterolemia was not observed in this study, suggesting these clinical markers may not be directly modulated by MMF's antifibrotic action in this context.
