A closer insight into the molecular effect of canagliflozin on gentamicin–induced nephrotoxicity in rats: attention to SIRT1/Nrf2/HO-1, p38 MAPK/NF-κB signaling pathways, and expression of miR-21 and miR-155

Abstract

Abstract Objective: Nephrotoxicity is considered the most detrimental effect of gentamicin (GM). In this study, we investigated the potential effects for canagliflozin (CANA) to protect against GM-induced nephrotoxicity, besides the multiple molecular pathways underlying these effects. Methods: Four groups with six rats in each were used: control; GM (100 mg/kg, intraperitoneal injection) for 7 days; CANA + GM group: Rats were given CANA (10 mg/kg, by oral gavage) for 14 days, and GM (100 mg/kg, by IP) was co-administered with CANA in the last 7 days; and CANA group: Rats were given CANA (10 mg/Kg, by oral gavage) for 14 days. Results: Relative to GM-challenged rats, CANA ameliorated GM-induced changes in the state of oxidative stress. Also, CANA alleviated the GM-evoked reduction in the renal expression of SIRT1 and Nrf2. Furthermore, CANA decreased the renal expression of NF-ҡB and reduced p38-MAPK levels in kidneys of GM-treated animals. Simultaneously, GM-induced changes in the renal expression of miR-21 and miR-155 have been successfully amended by CANA. Conclusion: Altogether, current outcomes imply that modification of the SIRT1/Nrf2/HO-1, the p38-MAPK/NF-ҡB pathways, and microRNAs (miRNAs) play an important role adressing CANA’s ‘protective properties against GM nephrotoxicity. Graphical AbstractFlowchart illustrating Canagliflozin's effects on three pathways: Sirt1/Nrf2/NF-?B, p38-MAPK/NF-?B, and microRNAs related to Gentamicin-induced nephrotoxicity.The flowchart presents three panels illustrating Canagliflozin's impact on pathways involved in Gentamicin-induced nephrotoxicity. The top section covers the Sirt1/Nrf2/NF-?B pathway, showing interactions among Sirt-1, Nrf2, and NF-?B, highlighting antioxidant effects. The middle section details the p38-MAPK/NF-?B pathway, emphasizing its role in inflammation and apoptosis. The bottom section focuses on microRNAs, depicting their mediation of Bcl-2 and apoptotic factors. Each panel summarizes Canagliflozin's antioxidant, anti-inflammatory, and anti-apoptotic actions on these pathways.