Empagliflozin and neohesperidin protect against methotrexate-induced renal toxicity via suppression of oxidative stress and inflammation in male rats.

Kidney injury from chemotherapy is one of the worsening problems associated with methotrexate (MTX) use. This work aims to examine the nephroprotective effects of empagliflozin (EMPA) and neohesperidin dihydrochalcone (NHD) provoked by MTX. A rat model was implemented by a single administration of MTX (20 mg/kg, i.p.). EMPA and NHD were administered in two doses (10 and 30 mg/kg, p.o.) and (40 and 80 mg/kg, p.o.), respectively for 14 consecutive days, using N-acetylcysteine (150 mg/kg, p.o.) as a reference standard. Pretreatment with EMPA and NHD showed significant attenuation in the renal function biomarkers, histopathological abrasions, and renal oxidative parameters. Also, EMPA and NHD pretreatment produced marked reductions in the expression of IL-6 and TNF-α level as proinflammatory biomarkers. Furthermore, EMPA and NHD pretreatment revealed marked decreases in the expression level of NF-ĸB, Keap1, HSP70, and caspase-3 and notable increases in Nrf2, PPARγ and HO-1 expression levels. EMPA and NHD can constrain oxidative stress liberation, inflammatory mediators proliferation, and apoptotic reactions in the renal tissue, which may be promising for further clinical applications to protect against MTX-induced renal injury or at least to reduce its adverse effects. [Display omitted] • Empagliflozin and Neohesperidin mitigated methotrexate-induced increase of serum creatinine and urea. • Empagliflozin and Neohesperidin attenuated the renal histopathological injury. • Empagliflozin and Neohesperidin downregulated renal TNF-α and IL-6 expression. • Empagliflozin and Neohesperidin suppressed renal NF-ĸB/Keap1/HSP-70/caspase-3 expression. • Empagliflozin and Neohesperidin induced renal Nrf2/PPARγ/HO1 expression. [ABSTRACT FROM AUTHOR]