الفهرس 
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Abstract
Acute renal failure is characterized by a rapid, potentially reversible, decline in renal function including rapid fall in glomerular filtration rate (GFR) and retention of nitrogenous waste products over a period of hours or days. It progresses to chronic kidney disease, end-stage renal disease and leads to multi-organ dysfunction. It associated with high morbidity, mortality, and healthcare costs.
Glycerol-induced ARF is characterized by myoglobinuria, tubular necrosis. The pathogenic mechanisms involved in glycerol-induced renal failure include ischemic injury, tubular nephrotoxicity caused by myoglobin, and the renal actions of cytokines released after rhabdomylosis.
Guanosine a purine nucleoside and considered an attractive agent for treatment of acute renal failure as it has various beneficial effects such as GTP salvage by exogenous administration of guanosine reduced renal tubular cell apoptosis, an effect that was associated with inhibition of p53 expression, improving renal blood flow through atriopeptin and nitric oxide which mediated by cyclic GMP, and it has been reported that inhibition of cyclic GMP phosphodiesterase with zaprinast increases renal blood flow and ameliorates ARF.
Cystatin C is a member of the cystatin superfamily of cystine protease inhibitors, produced by all nucleated cells of the body and released into the bloodstream at a constant rate. Serum cystatin C concentrations are independent of age, sex, race, body mass and hydration level. Its expression is induced by a number of factors including oxidative stress which considered one of mechanisms occurs in acute renal failure.
Klotho is a transmembrane protein that acts as a co-receptor for fibroblast growth factor-23. In the renal tubule, klotho modulates sodium-phosphate co transporters, calcium channels and potassium channels. Klotho gene is expressed in multiple tissues, the kidney being the organ where it is expressed more markedly. Its expression is downregulated by renal ischemia.
The goal of this study is to show the effect of guanosine on altered renal function associated with glycerol induced ARF and to reveal its mechanism through its effect on expression of cystatin C and klotho in kideny tissue.
In current study rats were divided into three groups control group was injected intramuscular with normal saline of 0.9% NaCl once and left for 6 weeks until sacrificed, glycerol induced ARF group as ARF is induced by a single intramuscular injection (2ml) of glycerol (50%) equally distributed to both hind legs, guanosine treated group was injected intraperitoneal with guanosine (1ml) daily for 2 weeks before induction of ARF as in glycerol induced ARF group then completed for one month after glycerol induction.
In all groups, serum level urea and creatinine were measured. Kidney tissue sections were stained by H&E to examine histopathological changes. Tissue alkaline phosphatase activity and tissue total antioxidant capacity were measured. The kidney tissue was analyzed for cystatin C gene expression and klotho gene expression using Real Time RT- PCR. Finally, immunohistochemistry by immune-histochemical staining of caspase 3 in kidney specimens was examined.
Our results showed that glycerol induced ARF causing marked elevation in the serum level of urea and creatinine. Guanosine could reduce them in a significant manner in addition it improved the histological alterations.
Also our results showed that glycerol induced ARF causing increase in tissue alkaline phosphatase activity while causing decrease in tissue total antioxidant capacity. Guanosine could decrease tissue alkaline phosphatase and increase tissue total antioxidant capacity.
Also acute renal failure was associated with up-regulation in the expression of cystatin C gene and downregulation in the expression of Klotho gene in kidney tissue while guanosine down-regulated the expression of cystatin C gene and up-regulated the expression of klotho gene in kidney tissue.
Additionally, immuno-histochemical staining for caspase 3 in kidney sections mostly increased in glycerol induced ARF group but it was obviously decreased in guanosine treated group.
The results explain effect of guanosine in glycerol induced acute renal failure as it improved the histological alterations in kidney, normalizes expression of renal cystatin C and klotho in acute renal failure in parallel with reducing serum urea and creatinine level.
We concluded that guanosine may be a promising platform in treatment of ARF may through increase klotho gene expression that helps in decrease of apoptosis with oxidative stress with increase total antioxidant capacity.