Protective effect of empagliflozin against paracetamol-induced acute kidney injury through modulation of AMPK/SIRT1/PGC-1α pathway in experimental mice

Abstract

Emerging evidences about paracetamol-induced kidney injury in clinical settings are concerning, especially when administered at high doses. Empagliflozin, an oral SGLT2 inhibitor, employed in the management of diabetes mellitus, exhibits antioxidant, anti-inflammatory, and anti-apoptotic attributes. Thus, the objective of this study is to investigate whether empagliflozin may alleviate paracetamol-triggered nephrotoxicity and unravel the mechanistic insights responsible for its protective impact. In this regard, male mice were assigned to four groups: normal, paracetamol, empagliflozin 10, and empagliflozin 20. Kidney function tests, histopathological examination, immunohistochemistry, oxidative stress biomarkers, inflammatory cytokines, and other molecular targets were detected. Our results showed that paracetamol administration impaired kidney functions along with causing aberrations in renal histoarchitecture. Additionally, paracetamol triggered oxidative stress, inflammation, and apoptosis via hindering the AMPK/SIRT1/PGC-1α cascade and Nrf2/HO-1 while activating the NF-κB hub. Nevertheless, pretreatment with empagliflozin markedly enhanced the kidney function tests and mitigated histopathological alterations caused by paracetamol. Additionally, empagliflozin suppressed the oxidative stress as confirmed by an upregulation of Nrf2, which subsequently increased HO-1, SOD, and GSH, while reducing the MDA level. Moreover, it inhibited the NF-κB-mediated inflammatory process by dampening NF-κB, IL-1β, and TNF-α expressions as well as lowering Bax expression-induced apoptosis. The observed safeguards effects were facilitated via boosting AMPK/SIRT1/PGC-1α signaling trajectory. Collectively, our study verified the enduring reno-protective potential of empagliflozin, particularly at high dose, in the context of paracetamol-induced renal injury by instigating the AMPK/SIRT1/PGC-1α hinge.