الفهرس 
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Abstract
The present study was undertaken to investigate the nephroprotective effect of grape and / or guava seeds extracts on gentamicin – induced nephrotoxicity in rats. Rats were divided into eight experimental groups. group 1 (control group) was injected intraperitonealy with saline solution; Groups (2, 3 and 4 were administrated a daily oral dose of grape (40mg/kg/d p.o), guava seeds extracts (300mg/kg/d p.o) or mixture of both, respectively; to demonstrate their safety. group 5 was intoxicated with gentamicin (100mg/kg/day i.p). Groups (6, 7 and 8) received oral dose of grape (40mg/kg/d p.o), and / or guava seeds extracts (300mg/kg/d p.o) along with intraperitonealy injection of gentamicin to investigate the beneficial effect of these extracts against gentamicin nephrotoxicity for a period of consecutive 10 days.
At the end of treatment period, 10 days (24 hours after the last injection), and the animals were kept individually in metabolic cages. Body weight of rats, absolute and relative kidney weights were determined. The following parameters were measured: serum level of creatinine, urea and uric acid. Serum levels of total protein, sodium, potassium, activity of alkaline phosphatase and glutathione (GSH). Renal content of malondialdehyde (MDA), nuclear factor kappa (NF) glutathione (GSH) and kidney injury molecule-1 (KIM-1), also, activity of erythrocyte Cu, Zn-SOD was determined. Histological examination of renal sections was also carried out.
The results of the present study can be summarized as follow:
1. Effect of grape seeds and /or guava seeds ethanolic extract on normal rats:-
• The obtained data demonstrated normal rats received grape seeds extract, guava seeds extract or mixed dose of both showed no significant changes in body weight change, absolute and relative weights of kidney as compared with negative control group.
• There were no significant effects on levels of serum creatinine, urea, total protein, sodium and potassium as compared with negative control. While Serum uric acid was significantly reduced in grape or guava seeds by18.7% and 23.7% respectively
• There were no statistically changes observed in renal kidney injury molecule -1 (KIM-1), blood GSH level, erythrocyte Cu, Zn –SOD activity and alkaline phosphates in normal rats received the tested extracts.
• The statistical result showed no significant changes in levels of renal reduced glutathione, malondialdehyde and nuclear factor kappa as compared with negative control.
• Microscopic examination of normal rats received grape seeds extract and / or guava seeds extract kidney cortex showed normal appearance of glomeruli and tubules.
• Kidney cortex showed normal positive PAS reaction along basement membranes and brush border of tubules.
2. Effects of grape and/ or guava seeds ethanolic extract on gentamicin treated rats:-
• The data showed that gentamicin injection resulted in significant increase in absolute (24.2%) and relative kidney weight (20.6%) as compared to negative control.
• The absolute kidney weight was significantly decreased by 12.6% in gentamicin injected rats treated by mixed dose of grape seeds and guava seeds extracts as compared with positive control. While, treatment of gentamicin injected rats with grape seeds extract or guava seeds extract had no significant effects on kidney weights. No considerable alterations were exhibited by relative kidney weights in gentamicin treated rats received the tested extracts or their mixture as compared to positive control.
• Gentamicin injection caused highly significant elevation in serum creatinine and urea reaching 10 and 8 folds, respectively as compared to negative control. On the other hand, neither serum uric acid nor total proteins were significantly affected by gentamicin injection as compared to negative control.
• The obtained data showed that treatment with the extracts of grape seeds and guava seeds or their combination attenuated gentamicin induced nephrotoxicity as evident from significant reduction in serum creatinine by 43.6%, 68% and 43% respectively, as compared with positive control. Moreover, serum urea was significantly decreased by 45% in gentamicin injected rats received guava seed extract.
• Furthermore, serum uric acid was significantly reduced by 20.7%, 28.5% and 39.2% respectively in gentamicin injected rats received the extracts of grape seeds or guava seeds or their combination as compared with positive control. While, no considerable alterations were exhibited in serum total protein in gentamicin treated rats received grape seeds extract and / or guava seeds extract.
• The result revealed that serum ALP activity was significantly elevated in gentamicin injected rats as compared with negative control. This elevation was significantly reduced only in the group received grape seeds extract. However oral administration of guava seeds extract or mixture of grape seeds and guava seeds extracts caused non significant reduction in serum ALP as compared with positive control.
• Renal kidney injury molecule-1 (KIM-1 gene expression was highly significantly elevated (447%) in groups injected with gentamicin as compared with negative control. Oral administration of grape seeds extract, guava seeds extract or their combination ameliorated and reduced this intense elevation by 56%, 67%and59%, respectively, as compared to positive control.
• The results presented clarify that administration of gentamicin caused a significant decrement in blood GSH level and erythrocyte Cu, Zn-SOD activity by 20% and 30%, respectively, as compared with positive control, This reduction in blood GSH and erythrocyte Cu, Zn –SOD activity was significantly improved in the groups received grape seeds extract, guava seeds extract and their mixture as level of blood GSH was significantly increased by 41.6%, 48.5% and 21.4%, respectively. Meanwhile erythrocyte Cu, Zn-SOD activity was significantly increased by 31.3% and 40.2% in the groups treated with the extracts of grape seeds or guava seeds.
• The data showed that gentamicin injection caused a significant reduction in renal level of reduced glutathione by (33.7%) as compared to negative control this reduction in renal antioxidant status was accompanied by considerable elevation in renal lipid peroxidation as shown by significant higher level of renal MDA in gentamicin intoxicated animal as compared to negative control. The altered levels of renal GSH and MDA were restored with administration of grape seeds extract, guava seeds extract or their mixture. The level of renal GSH was significantly increased by 40.7%, 29.1% and 27%, respectively, whereas the level renal MDA was significantly decreased by 38.5%, 40% and 41.7%, respectively, as compared with to gentamicin treated rats.
• Renal nuclear factor kappa was highly significantly elevated (557%) in gentamicin intoxicated animals as compared with normal rats. This elevation was significantly alternated by administration of the ethanolic extracts of grape seeds or guava seeds and combination of ethanolic extracts (58%, 60% and 63.9, respectively) as compared positive control.
• Gentamicin injection resulted in significant reduction in serum levels of sodium 10.7% and potassium 10.2% comparing with negative control. Treatment of nephrotoxic rats with extracts of grape and/ or guava seeds nearly normalized serum sodium. Serum potassium level was significantly reduced in gentamicin injected rats received guava seeds extract as compared to positive control.
• Gentamicin injection resulted in significant elevation levels of serum triacylglycerol and cholesterol by (73%and 13.2 respectively) as compared to normal rats.
• Gentamicin treated rats received grape seeds extract showed significant increase in HDL-cholesterol by 35% compared to positive control.
• Treatment of gentamicin injected rats with grape seeds extract or the combined extract normalized LDL-Cholesterol and significantly reduced by 16% and by 22% respectively as compared to positive control.
• Histological changes of kidneys cortex exposed to gentamicin appeared in hydropic degeneration in tubules, acidophilic casts in tubules, congestion of blood vessels and lymphocytic infiltration dilated tubules with flattened epithelium or loss of cells filled with acidophilic casts showed
• Kidney cortex and medulla in gentamicin treated rats received grape seeds extract and /or guava seeds extract showed less damage in renal tubules compared to gentamicin group.