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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 (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., (Copyright 2003 S. Karger AG, Basel)

Background/aims: In the rat Adriamycin model of chronic renal failure, the development of glomerulosclerosis and tubulointerstitial lesions is accompanied by decreased activities and mRNA levels of the antioxidant enzymes. In this study, we investigated the effect of oral vitamin E supplementation on antioxidant enzyme activities in both the cortex and isolated glomeruli from Adriamycin-treated rats., Methods: Glomerulosclerosis, tubulointerstitial lesions and ferric iron deposits were evaluated by histochemical staining methods, and antioxidant enzyme activities were measured by spectrophotometry., Results: Vitamin E supplementation of the normal diet attenuates Adriamycin-induced glomerulosclerosis and tubulointerstitial lesions, but not proteinuria and serum total cholesterol, low-density lipoprotein cholesterol, triglycerides and total protein concentrations. In the cortex, vitamin E completely prevented a decrease in enzyme activity for Cu/Zn superoxide dismutase and catalase, and partly for Mn superoxide dismutase and glutathione peroxidase. In the glomeruli, vitamin E completely prevented a decrease in activity for Cu/Zn superoxide dismutase, catalase and glutathione peroxidase, and partly for Mn superoxide dismutase., Conclusion: Dietary supplementation of vitamin E protects the activities of antioxidant enzymes in the kidney cortex and glomeruli, and attenuates the evolution towards terminal renal failure in rats treated with Adriamycin., (Copyright 2002 S. Karger AG, Basel)

Angiotensin II administration to rats during 6 weeks causes decreased activity of catalase and glutathione peroxidase in renal cortex. Rats show mild hypertension, subclinical signs of renal injury, increased glomerular expression of desmin, glomerular and interstitial expression of alpha-smooth muscle actin and an increased number of ED-1-positive cells in glomeruli. An inverse correlation exists between catalase activity and glomerular alpha-smooth muscle actin expression and between glutathione peroxidase activity and glomerular desmin expression. The decrease of antioxidant enzyme activity, early after angiotensin II administration, might be an important initiating factor in the complex process leading eventually to renal sclerosis by reduction of reactive oxygen intermediate breakdown. The significant relationship between markers of sclerosis and some antioxidant enzyme activities suggests either a causative link or a common triggering factor., (Copyright 2001 S. Karger AG, Basel)

Excessive generation of reactive oxygen intermediates can induce changes in the cellular antioxidant defence system. In this study we examine the antioxidant enzyme status and the expression of fibrosis-related marker proteins in the Adriamycin model of chronic renal failure in the rat. Twenty weeks after Adriamycin treatment, rats have overt nephrotic syndrome and renal failure with development of tubulo-interstitial fibrosis and glomerulosclerosis. Lipids accumulate in blood and in both glomeruli and tubulo-interstitial tissue. Desmin and alpha-smooth muscle actin expression increases in glomeruli and in the tubulo-interstitial area. Renal cortex antioxidant enzyme activities are decreased 20 weeks after Adriamycin injection (to 41% for catalase, to 56% for total superoxide dismutase and to 69% for glutathione peroxidase). The mRNA levels of catalase, Cu/Zn-superoxide dismutase and glutathione peroxidase-1 evaluated by Northern blot are decreased by more than 50% for catalase, Cu/Zn-superoxide dismutase and glutathione peroxidase-1. We conclude that in the rat Adriamycin-induced model of chronic renal failure with fibrosis, the combination of decreased antioxidant enzyme status in renal cortex with high concentrations of lipids in blood and renal tissue facilitates oxidative damage. Development of fibrosis is paralleled by increased expression of desmin and alpha-smooth muscle actin.

Reactive oxygen intermediates play a role in chronic renal injury and glomerulosclerosis. We investigate changes in renal cortex antioxidant enzyme gene expression in the rat remnant-kidney model of chronic renal failure and compare the new data to enzyme activities published earlier. Antioxidant enzyme gene expression is evaluated by Northern blot analysis of cortex mRNA, using cDNA probes for catalase, copper/zinc-containing superoxide dismutase, and glutathione peroxidase. Catalase gene expression decreases during development of renal failure; this decrease is accompanied by decreased catalase activity during the glomerulosclerosis phase of the remnant-kidney model. Copper/zinc superoxide dismutase and glutathione peroxidase gene expression remain at a normal level during progression of the model, whereas their activities show a temporary decrease in the early remnant kidney. In the remnant-kidney model, catalase seems to be more vulnerable to reactive oxygen intermediates than superoxide dismutase and glutathione peroxidase. Our results show that antioxidant enzyme activity and gene expression do not change in the same direction at all times during disease development and that all antioxidant enzymes do not respond in the same way., (Copyright 2000 S. Karger AG, Basel.)

In rats with five-sixths nephrectomy (remnant kidney), blood pressure, glomerulosclerosis, and proteinuria are significantly reduced by administration of the angiotensin-converting enzyme inhibitor enalapril, during 16 weeks after reduction of the nephron number. The activity of catalase in remnant-kidney cortex homogenate is not influenced by enalapril treatment; the activities of superoxide dismutase and glutathione peroxidase are significantly increased. Elevated lipid peroxidation in cortex homogenates, evaluated by malondialdehyde and 4-hydroxynonenal concentrations, is not changed by treatment. Supplementation of dietary vitamin E to enalapril treatment does not alter antioxidant enzyme activities when compared to enalapril monotherapy. These results show that enalapril improves the balance between reactive oxygen intermediates and antioxidant enzymes in the remnant-kidney cortex of the rat. This finding may in part explain the protective effect of angiotensin-converting enzyme inhibitors on the progression of glomerulosclerosis.

In rats with five-sixth nephrectomy (remnant kidney), glomerulosclerosis was significantly reduced by dietary administration of vitamin E (alpha-tocopherol) during 11 and 16 weeks after reduction of nephron number. The activity of catalase and the production of H2O2 in remnant kidney cortex homogenate were not influenced by the vitamin E diet; however, the activities of glutathione peroxidase and superoxide dismutase were significantly increased (up to 140 and 180%, respectively, after 16 weeks). Lipid peroxidation, evaluated by malonaldehyde and 4-hydroxynonenal concentrations, was decreased in cortex homogenates and in urine. Though the extent of the effect of vitamin E on antioxidant enzyme levels and lipid peroxidation is small, the important reduction of glomerulosclerosis is in favor of dietary supplementation with vitamin E.

Nephron loss leads to increased production of reactive oxygen intermediates. We measured the effect of carvedilol, a beta-blocking drug with radical scavenging properties, on renal function, glomerulosclerosis, antioxidant enzyme status and in vivo hydrogen peroxide (H2O2) production in rats with chronic renal failure caused by 5/6 nephrectomy (remnant kidney) and compared results to data obtained with propranolol, a beta-blocking drug without scavenging characteristics. Carvedilol and propranolol were administered during 11 weeks following reduction of nephron number. Kidneys were examined using enzymatic and histological techniques. Both carvedilol and propranolol decreased systolic blood pressure. Compared to propranolol, carvedilol offered some additional beneficial effects on renal function, particularly with regard to glomerulosclerosis. Lipid peroxidation, evaluated by malonaldehyde and 4-hydroxynonenal concentration in cortex homogenates, was decreased in carvedilol-treated rats only. Superior beneficial effect of carvedilol treatment is not linked to a significant up-regulation of the activities of the remnant kidney antioxidant enzymes (catalase, glutathione peroxidase and superoxide dismutase) or to a decreased in vivo H2O2 production.

In the rat remnant kidney hydrogen peroxide (H2O2) production is increased when compared to the normal kidney. The activities of the peroxisomal H2O2-producing oxidases, D-amino acid oxidase and acyl-coenzyme A oxidase, and of the extraperoxisomal superoxide dismutase are decreased in renal homogenate. The peroxisomal L-alpha-hydroxyacid oxidase and L-lactate oxidase as well as the peroxisomal H2O2 scavenger catalase preserve their activity. The activity of the cytosolic scavenging system, glutathione peroxidase, is decreased by 40%. A starvation period of 48 h does not produce a measurable increase in H2O2 production in the normal nor in the remnant kidney. On visual inspection, peroxisomal morphology and distribution in the renal tubules are similar in the normal and remnant kidney tissue.