الفهرس 
Introduction and Aims of the workOnly 14 pages are availabe for public view
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Abstract
Aminoglycoside are broad group of antibiotics that employed as effective drugs for management of numerous infections, caused by gram negative and gram positive bacteria. Aminoglycoside has no substitute in the therapy of infections especially which resulted from highly resistant bacterial strains.
GEN is one of the most important members of this class of antibiotics. Unfortunately, GEN-induced nephrotoxicity limited its clinical utility. Although the pathologic process of nephrotoxicity was extensively studied, the underlying mechanisms are not yet completely explained.
Several studies suggested that nephrotoxicity induced by GEN is due to increase of ROS and decline in antioxidant defense mechanisms. Abundant literature is reporting that ROS can stimulate TGF-β signaling pathway. TGF-β1, a type of cytokine that appears to be a primary molecule in the induction of EMT, however the number of inducers and pathways involved in EMT is still emerging.
EMT is a highly conserved biological program in which epithelial cells attain the specific characters of mesenchymal cells. While EMT in embryonic development is highly structured and organized process, the inappropriate activation of EMT in response to aberrant stimuli or alterations in microenvironment can lead to tissue fibrosis. EMT is hallmarked with decrease of the expression of E-cad epithelial marker and increase of the α-SMA mesenchymal marker. The pathologic process of nephrotoxicity caused by GEN may involve EMT.
RES is a widely known polyphenol contained abundantly in red grapes, has been known to be a potent antioxidant. RES was revealed to inhibit EMT in many types of cancers and kidney diseases.
This study aims to:
1) Relate the initiation of EMT activation and the onset of GEN-induced nephrotoxicity
2) Evaluate the possible renoprotective impact and signaling pathway of RES action against GEN-induced EMT.
The current experimental study consisted of two parts:
The first part was conducted to determine the onset of EMT in relation to GEN-induced nephrotoxicity. Mice were divided into five groups. group 1: control, group 2: was administrated GEN for 3 days, group 3: was administrated GEN for 5 days, group 4: was administrated GEN for 8 days and group 5: was administrated GEN for 15 days.
The second part was conducted to investigate the effects of RES on EMT caused by GEN. Mice were divided into five groups. group 1: control, group 2: was administrated RES for 22 days, group 3: was administrated GEN for 15 days, group 4: was administrated low dose RES for 7 days followed by administration of low dose of RES and GEN for 15 days. group 5: was administrated high dose of RES for 7 days followed by administration of high dose of RES and GEN for 15 days.
After administration of the last dose of either GEN and /or RES, mice were separately housed in clean metabolic cages in order to obtain 24-h urine samples. Animals were sacrificed to obtain blood and tissue samples. Weight of each kidney was registered. Blood and urine samples were utilized for assessment of kidney function tests. Right kidney was divided longitudinally into two parts; one of them was fixed in Davidson’s solution for immunofluorescence and histopathological examination, while the other was kept at – 80 °C for western blotting analysis. Left kidney was homogenized and tissue homogenate was used for assessment of oxidative stress markers.
GEN administration significantly deteriorated kidney functions. In addition, GSH content and CAT activity were significantly decreased with a concomitant increase in the content of kidney MDA after GEN treatment. Histological changes and deposition of collagen were extensive in renal corpuscles and tubules. Increased expression of -SMA, TGF-β1 and p-Smad2 were observed after GEN administration, while E-cad expression was decreased. On the contrary, pretreatment with both doses of RES reversed the modifications caused by GEN administration.
We elucidated that EMT contributes to pathogenesis of GEN-induced nephrotoxicity. RES has a significant protective effect on GEN-induced EMT via suppressing oxidative stress and TGF-β/Smad signaling pathway.