الفهرس 
Introduction and aim of the workOnly 14 pages are availabe for public view
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Abstract
In this study, we investigated the nephroprotective role of SGLT-2 inhibitor, empagliflozin, against gentamicin-induced nephrotoxicity and the possible mechanisms underlying this effect.
Acute kidney injury was induced by intraperitoneal administration of gentamicin (100 mg/kg/day) for 8 days. Male Wistar rats were divided into five groups (8 rats each);
• Control rats received 0.5 ml normal saline i.p. and 0.5 ml 0.5% CMC P.O.
• Gentamicin group: Rats received gentamicin 100 mg/kg/day i.p. and 0.5 ml 0.5% CMC P.O.
• GM+EMPA10 group: Rats received gentamicin 100 mg/kg/day by intraperitoneal injection and empagliflozin (10 mg/kg/day P.O.).
• GM+EMPA20 group: rats received gentamicin 100 mg/kg/day by intraperitoneal injection and empagliflozin (20 mg/kg/day P.O).
• EMPA 20 group: rats received 0.5 ml normal saline I.P. and empagliflozin (20 mg/kg/day P.O).
All animals were treated for 8 days then 24h after the last dose, all animals were sacrificed, blood samples and renal tissues were collected.
To fulfil the aim of this study, different parameters have been assayed including kidney function parameters (serum creatinine, urea, and cystatin c concentrations), concentration of gentamicin in kidney tissues and in the serum, oxidative stress markers including; MDA level, TAC, CAT, and SOD, as well as inflammatory, apoptotic, and fibrotic markers in renal tissues including; NF-κB, caspase-3, and TGF-β. In addition, PAX-2, a marker of tubular regeneration and the epigenetic regulator sirtuin 1 levels were assayed. Histopathological evaluation of renal section from each group was performed to confirm the data obtained from biochemical analysis.
The present study demonstrated the following results;
• Administration of gentamicin (100 mg/kg) successfully induced acute renal injury as evidenced by increased serum creatinine, urea, and cystatin c levels as well as histopathological changes observed in H&E-stained sections including; marked tubular necrosis and apoptosis mainly of proximal tubular cells. Cotreatment with either dose of empagliflozin abrogated the gentamicin induced renal damage with nearly normalized renal function and structure in the group treated with the higher dose of empagliflozin.
• Gentamicin administration increased lipid peroxidation (MDA level) in renal tissue as well as decreased total antioxidant capacity, SOD, and catalase activity. The oxidative stress induced by gentamicin was alleviated by concomitant administration of empagliflozin.
• In gentamicin-treated group, the markers of inflammation, apoptosis, and fibrosis (NF-κB, caspase-3, and TGF-β1 respectively) were elevated in renal tissues while their levels were significantly lowered in empagliflozin-treated groups.
• Renal levels of PAX2, a marker of tubular regeneration, was elevated in group treated with empagliflozin (20 mg/kg). However, treatment with empagliflozin (10mg/kg) did not cause a significant change in renal PAX2 levels when compared to gentamicin group.
• Gentamicin administration decreased the level of sirtuin-1(SIRT1) while renal SIRT1 levels were elevated in the gentamicin group treated with empagliflozin (20mg /kg)
• Treatment with empagliflozin (20 mg/kg) decreased renal and serum gentamicin concentration while treatment with empagliflozin (10 mg/kg) decreased serum but not renal gentamicin concentration.
In conclusion, empagliflozin produced dose dependent nephroprotection against gentamicin-induced nephrotoxicity. Decreased gentamicin accumulation in renal tubular cells together with antioxidant, anti-inflammatory and antiapoptotic effects of empagliflozin may mediate its nephroprotective action. Empagliflozin mediated increase in renal level of SIRT1 and PAX2 may play a role in protection and recovery from gentamicin-induced AKI.