الفهرس 
REVIEW OF LITERATUREOnly 14 pages are availabe for public view
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Abstract
Ischemic ARF is a common clinical event leading to development of chronic kidney disease and transition from pre-existing chronic kidney disease to end-stage renal disease and a high mortality. There is an interaction between many cell types involved in the pathophysiology of ischemic acute renal failure, which has critical implications for the treatment of this condition. IRI is an unavoidable consequence of organ transplantation that may occur during a number of stages in the transplantation procedure. The inflammatory response involved in IRI can prime the organ for immune responses, thus contributing adversely to delayed graft function, allograft rejection and long term survival.
In the present study, the possible interaction between NO, COX-2 and ROS in the pathogenesis of ischemic acute renal failure was investigated. In addition, the potential protective effect of drugs acting on these pathways was also examined in the renal IRI model adopted. The investigated drugs included celecoxib as an example of COX-2 inhibitor and L-arginine as an example of NO donor and their combination. A complementary set of in-vitro experiments was performed in the present study using rat aortic rings to investigate the effect of the previous two drugs, as well as ascorbic acid, and their combinations on vasculature before and after hypoxia/reoxygenation.
Renal IRI was induced in male Sprague-Dawley rats by clamping both renal pedicles with non-traumatic vascular clamps for 45 minutes. Reperfusion was established by removing the clamps. Rats were fasted 18 hours before biochemical determinations. 24 and 48 hours after reperfusion, fasted rats were anaesthesized with ether and blood samples were obtained from the orbital plexus and collected into non-heparinized tubes. Centrifugation of blood samples was performed and serum was recovered and stored at -20oC for the determination of urea and creatinine.
After collecting blood samples, the two kidneys were removed. The right kidney was divided longitudinally into two halves; one was fixed in 10% formaldehyde saline solution and stained by “haematoxylin and eosin” stain (H&E) for histopathological examination. The other half together with the left kidney were homogenized with ice-cold saline to prepare a 40% homogenate which was stored at -80oC till used for the determination of kidney MDA, GSH, NO, COX-2 levels, SOD activity and total protein content. These parameters were measured in SO, IRI, and drug-treated groups of rats.
Hypoxia/reoxygenation was induced by submitting the aortic rings to 20 minutes of hypoxia by changing the gas mixture to 95% N2-5% CO2, followed by 30 minutes of reoxygenation by changing the gas mixture back to 95% O2-5% CO2. The effect of hypoxia/reoxygenation and the drugs under investigation was examined on the dose response curve of ACh and SNP of the aortic rings. The main findings of the present study can be summarized as follows:
1. Renal IRI, following bilateral clamping of renal pedicles for 45 minutes, was associated with impaired renal function manifested as marked increase in serum creatinine and urea levels and significant increase in oxidative stress parameters marked by an increase in the renal MDA level and reduced level of GSH and SOD activity. Renal IRI was associated with reduced NO bioavailability and elevated level of COX-2 enzyme. Histopathological examination revealed diffused tubular necrosis, areas of haemorrhage and the significant elevation of the histopathological score to 4 as compared to the SO groups. Similarly, hypoxia/reoxygenation impaired both endothelium-dependent and –independent relaxation of aortic rings.
2. Oral administration of selective COX-2 inhibitor, celecoxib, (10 mg/kg) for 7 days prior to IRI improved renal function, reduced oxidative stress, increased NO bioavailability and decreased COX-2 level in the kidney which suggests a role for COX-2, probably being a source of ROS in biological systems, in the pathogenesis of ischemic ARF. To our knowledge, this is the first study to report a positive role for celecoxib on oxidative stress associated with renal IRI. celecoxib significantly reduced the histopathological score compared to IRI group. In addition, celecoxib (2x10-7 M) potentiated endothelium-dependent and –independent relaxation of ischemic aortic rings.