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      Effect of Mycophenolate Mofetil on Glomerulosclerosis and Renal Oxidative Stress in Rats

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          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 (α-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 α-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 α-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.

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          A simple fluorometric assay for lipoperoxide in blood plasma.

           K Yagi (1976)
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            Mycophenolate mofetil attenuates renal injury in the rat remnant kidney.

            Mycophenolate mofetil (MMF), an inhibitor of lymphocyte proliferation, has been used to prevent allograft rejection. We investigated whether MMF also limits progressive renal injury in rats with 5/6 renal ablation, a model not primarily related to immunologic mechanisms. Eighty-eight adult male Munich-Wistar rats underwent ablation and received either vehicle (N = 42) or oral MMF (N = 46), 10 mg/kg/day. Forty-seven sham-operated rats were also studied. Thirty days after surgery, remnant kidneys exhibited glomerular hypertension and hypertrophy. MMF treatment did not correct these abnormalities. Immunohistochemistry revealed interstitial lymphocyte infiltration 7 and 30 days after ablation. Proliferating cells abounded seven days after ablation, especially in tubules, declining in number along the following weeks. By contrast, the number of macrophages was moderately increased in the first weeks, attaining values eightfold as high as control 60 days after ablation. MMF attenuated these cellular events at all phases of the study. Sixty days after ablation, marked albuminuria, glomerulosclerosis and interstitial expansion were prominent in untreated rats. MMF treatment largely attenuated glomerular and interstitial injury without changing proteinuria. This is the first evidence that MMF may impact favorably on progressive renal diseases of "nonimmunologic" origin.
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              Mycophenolate mofetil treatment reduces atherosclerosis in the cholesterol-fed rabbit.

              Immune/inflammatory responses of arterial vessel wall constituents to lipid metabolic disturbances have been postulated to contribute to the pathogenesis of atherosclerosis. Mycophenolate mofetil (MMF), an antiproliferative agent used in clinical transplantation, has been shown to inhibit smooth muscle cell (SMC) proliferation and decrease the recruitment of monocytes into sites of chronic inflammation. This study was conducted to determine the effect of MMF on atherosclerotic plaque development after cholesterol-induced injury. New Zealand white rabbits were fed a high-cholesterol diet containing 0.5% cholesterol and 8% peanut oil. The experimental group (n = 10) was given MMF (80 mg/kg/day subcutaneously); the control group (n = 10) received placebo injections. The aortas were harvested at 12 weeks for immunohistochemical analyses. SMCs were identified by reactivity with a monoclonal antibody (mAb) to alpha smooth muscle actin. Monocytes/macrophages were detected with mAb RAM 11. Cross-sectional areas of the media and neointima were measured using computer-assisted image analysis. The density of SMCs and macrophage/foam cells within the neointima was calculated by dividing the number of cells by the area of the plaque. Total cholesterol, triglyceride, high density lipoprotein, and low density lipoprotein were significantly increased compared with levels before the initiation of a high-cholesterol diet, but there were no significant differences between the MMF-treated and untreated groups. Neointimal area in aortic tissue sections of the MMF-treated group (0.586 +/- 0.602 mm(2)) was significantly lower when compared with that in control animals (1.082 +/- 0.621 mm(2)) (P < 0.05). The densities of neointimal SMCs and monocytes/macrophages in the control group were 778 +/- 293 and 341 +/- 90 cells/mm(2), respectively. MMF treatment significantly reduced the number of neointimal SMCs (506 +/- 185 cells/mm(2)) (P < 0.05). The number of monocytes/macrophages was also reduced after MMF treatment (260 +/- 124 cells/mm(2)) but not significantly. Our results demonstrate that the administration of MMF significantly reduced neointimal SMC accumulation and plaque development in a hypercholesterolemic model of atherosclerosis.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                November 2003
                17 November 2004
                : 95
                : 3
                : e93-e99
                Departments of aHuman Anatomy and bNephrology, Vrije Universiteit Brussel (VUB), Brussels, Belgium
                74325 Nephron Exp Nephrol 2003;95:e93–e99
                © 2003 S. Karger AG, Basel

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                Figures: 3, Tables: 3, References: 20, Pages: 1
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