Study on the Possible Protective Effects of Dapagliflozin Against 5-Fluorouracil-Induced Renaltoxicity in Rats

Abstract

Background: 5-FU remains a challenging drug in clinical practice because it induces tissue injury, especially in the renal tissue, through activation of oxidative stress, inflammation, and the apoptotic pathway. In contrast, Dapagliflozin (DAPA) is a sodium-glucose inhibitor (SGLT2), an antidiabetic drug used in a large portion of individuals globally because it has antidiabetic, anti- inflammatory, and antioxidant properties. Dapagliflozin demonstrates nephroprotective effects by reducing renal injury through ameliorating oxidative stress, inflammation, and the apoptotic pathway. The aim of this study is to assess the nephroprotective effect of Dapagliflozin in mitigating 5-fluorouracil toxicity by measuring several oxidative stress, inflammatory, and apoptotic biomarkers in rats.
Methodology: In the research, 48 male albino rats were split into six groups (n = 8): G1 (control) received regular saline (1 ml/kg/day). intraperitoneal IP injection; G2 (induction) got a single intraperitoneal dose of 5-FU 100 mg/kg completed with(1ml/kg/day) of normal saline; G3 received 5 mg/kg/day oral dapagliflozin; G4 received the single dose of 5-FU (100mg/kg) intraperitoneal with (5mg/kg) daily of Dapagliflozin orally. G5 received the 10mg/kg daily of Dapagliflozin orally, G6 received the single dose of 5-FU 100mg/kg intraperitoneal with (10mg/kg) daily of Dapagliflozin. At the end of the experiment (after 6 weeks), rats were anesthetized and euthanized. serum sample collected for determination of serum urea, creatinine by using coulometric methods, and IL-1 & IL-10 by ELISA. Kidney tissue for each rat was harvested; a portion was stored in PBS till homogenized to evaluate GSH and MDA markers by ELISA, while another part was stored at 10% of formalin for histopathology study and IHC to assess Caspase-8 and MYD88 proteins expression.
Results: 5-FU caused renal injury, as evidenced
by elevated serum urea and creatinine levels, MDA and IL-1β biomarkers, and decreased GSH and IL-10. In kidney tissue, histopathological changes after 5-FU induction are associated with upregulation of both caspase-8 and myeloid88 proteins. Meanwhile, rats in groups 4 and 6 were treated with 5-FU plus DAPA, especially at 10mg/kg, which showed amelioration of kidney injury changes and oxidative stress markers, as well as improved histopathological appearance with preserved renal tissue with a reduction of expression of both caspase-8 and myloid88.
Conclusions: Dapagliflozin has a protective effect to reduce 5-FU therapeutic effects that induced renal injury in rats, through ameliorating oxidative stress, inflammation, apoptotic markers, and histopathological modifications. These findings suggest that Dapagliflozin exerted a strategy to reduce 5-FU toxicity.