الفهرس 
Introduction and Aim of the WorkOnly 14 pages are availabe for public view
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Abstract
Nephrolithiasis is a widespread disease influencing about 10% of the world population and is considered one of the most painful diseases. The prevalence of nephrolithiasis has elevated over the preceding years due to altering dietary habits, increasing obesity, and global warming. The recurrence rates of nephrolithiasis rise to 50% of stone patients in epidemiological studies. Hence, it is urgent to search for new strategies for treatment and prevention of recurrent kidney stone disease. Although the definite mechanism of stone development is not entirely understood, oxidative stress is confirmed to have an obvious role in the development of nephrolithiasis. Reactive oxygen species (ROS) are generated through the interaction between oxalate/calcium oxalate monohydrate (COM) crystals and renal cells and are blamed for the several cellular responses by stimulating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase which is a significant source of ROS in kidney cells during stone development. Consequently, drugs that reduce oxidative stress are good candidates to prevent nephrolithiasis. Sodium thiosulfate (STS), an FDA-approved drug used to reduce adverse reactions to cisplatin and in the emergency treatment of cyanide poisoning, has been proposed as a potential antiurolithiatic agent due to its electron donation and scavenging potential for free radicals. In addition, oxalate and COM trigger the renin–angiotensin system (RAS). Inflammatory response and oxidative stress are augmented by local angiotensin production. Renal cell injury and ROS stimulate transforming growth factor beta (TGF-β) secretion. TGF-β, profibrotic cytokine, is up-regulated in chronic kidney diseases leading to glomerulosclerosis and tubulointerstitial fibrosis. Different types of renal cells go through diverse pathophysiological changes induced by TGF-β, leading to apoptosis and hypertrophy, which eventually result in renal dysfunction. The angiotensin receptor blocker used as blood pressurelowering agent candesartan (CAND), has also been proposed as an antiurolithiatic agent. It was stated that kidneys of hyperoxaluric rats treated with candesartan, showed less calcium oxalate stones, and reduced oxidative stress biomarkers. Indeed, CAND has been shown to protect the kidney from oxidative stress injury by inhibiting ROS generation and tubulointerstitial inflammation. Furthermore, it has shown significant role on stone development in the kidney by lowering NADPH oxidase and TGF-β levels. The objective of the current study was to examine the possible protective role of CAND and STS against nephrolithiasis and to elucidate the underlying biochemical mechanisms. Nephrolithiasis was induced by ethylene glycol which is commonly used to form nephrolithiasis model in rats to simulate the formation of kidney stones in humans. As a positive control, we used the antiurolithiatic drug cystone (CYS) which is herbal formulation used to treat and preclude urinary tract infection and kidney stone formation. Rats were weighed and divided randomly into five groups: • Normal control group (water ad libitum) • Nephrolithiasis (EG) group (1% EG in drinking water) • Cystone (CYS) group (1% EG in drinking water + 750 mg/kg CYS, orally, once daily). • STS group (1% EG in drinking water + 0.4 gm/kg STS, intraperitoneally, 3 times/week). • CAND group (1% EG in drinking water + 70μg/mL CAND in drinking water). Treatments and EG administration started on the same day and lasted for 28 days. Cystone was employed as reference drug. Urine, blood, and kidney tissues were collected at the end of the experiment for assessment of kidney function tests (serum creatinine and urea), urinary (8-hydroxydeoxyguanosine (8-OHdG), calcium and oxalate), inflammatory and oxidative stress biomarkers (transforming growth factor beta (TGF-β), osteopontin (OPN) and ratio of reduced glutathione to oxidized glutathione (GSH/GSSG)) in renal tissue. The obtained findings showed that serum (creatinine and urea), urinary (8-OHdG and oxalate) and renal (OPN and TGF-β) concentrations were significantly increased in EG group compared to normal control. Moreover, renal GSH/GSSG and urinary calcium were significantly decreased in EG group compared to normal control group. Histopathological examination of kidney sections of EG group showed severe tubular cell degeneration, necrosis and fibrosis. They also showed moderate inflammation and severe intratubular deposition of crystals. Microscopic examination of urine samples of EG group showed abundant CaOX crystals. Moreover, our results revealed that serum (creatinine and urea), urinary (8-OHdG and oxalate) and renal (OPN and TGF-β) concentrations were significantly reduced in CAND and STS groups when compared to EG group. Furthermore, renal GSH/GSSG and urinary calcium were significantly increased in CAND and STS groups when compared to EG group. Histopathological results support the biochemical findings; CAND and STS groups showed less retention of crystals and necrotic damage in kidney. Also, microscopic examination of urine showed less crystal for CAND and STS groups. CYS group significantly reduced serum urea to normal level but serum creatinine reduction was still significantly different from normal control. Effect of CYS on measured urinary biochemical parameters (oxalate and calcium) and on renal OPN and TGF-β concentrations was non-significantly different from CAND and STS groups. Nonsignificant effect from EG group on oxidative stress biomarkers was observed in CYS group. Kidney sections of rats treated with CYS showed moderate tubular urolithiasis with moderate degree of nephritis and fibrosis. Microscopic examination of urine samples showed significant decrease in CaOX crystals number. Conclusion Candesartan and sodium thiosulfate showed protective effect against nephrolithiasis. In the present study, candesartan and sodium thiosulfate exerted anti-inflammatory, antioxidant effects and protected against calcium oxalate renal calculi formation in EG nephrolithiasis rat model. On the molecular level, both drugs decreased the level of the fibrotic mediator TGF-β, the inflammatory mediator OPN and oxidative stress (clearly observed by high GSH/GSSG and low 8-OHdG). Treatment with either candesartan or sodium thiosulfate in prophylactic regimen could correct the deterioration of renal tissue histopathology and function. Therefore, they could be considered a promising strategy in preventing recurrent kidney stones. Recommendations Further prospective studies are required to investigate whether the effects of candesartan or sodium thiosulfate are likely to be achieved in therapeutic regimens. Further studies are also warranted to examine the efficacy of candesartan or sodium thiosulfate in inhibiting the formation of renal calculi in clinical settings.