Alogliptin Attenuates Diclofenac‐Induced Acute Kidney Injury Associated With Activation of the AKT/Nrf2‐mediated Ferroptosis Pathway

Abstract

Ferroptosis, a regulated form of cell death, has emerged as a crucial player in acute kidney injury (AKI); yet its involvement in diclofenac (DIC)-induced nephrotoxicity remains poorly understood. Alogliptin, a dipeptidyl peptidase (DPP)-IV inhibitor, is known for its anti-inflammatory and antioxidant properties; however, its potential to counteract ferroptosis-driven renal damage has not been fully explored. This study, therefore, aims to investigate the role of ferroptosis in diclofenac-induced kidney injury and evaluate the potential renoprotective effect of alogliptin, along with revealing the underlying mechanism(s). Rats were randomly allocated into four groups that were treated with saline or alogliptin ( ± DIC) for 14 successive days. DIC administration resulted in significant kidney damage, as evidenced by remarkable rise in serum creatinine, urea, and renal content of kidney injury molecule-1, alongside notable histopathological changes. Alogliptin pretreatment markedly attenuated these alterations, restoring renal function and histoarchitecture. Furthermore, alogliptin offset DIC-triggered ferroptosis, as indicated by reduced renal iron content and ACSL4 levels, along with upregulation of ferritin, SLC7A11, and GPX4. Moreover, it alleviated renal lipid peroxidation (increased malondialdehyde), apoptosis (heightened caspase-3 and diminished Bcl-2 expression), oxidative stress (downregulated glutathione, superoxide dismutase), and inflammation (elevated IL-6 and TNF-α expressions) in a dose-dependent manner. The current study uncovers a novel renoprotective role for alogliptin in mitigating DIC-induced renal injury, potentially mediated by stimulating AKT/Nrf2/SCL7A11/GPX4 signaling axis, with subsequent dampening of lipid peroxidation and ferroptosis, besides its well-known, anti-inflammatory, and antiapoptotic actions. Finally, these findings provide compelling evidence for repurposing alogliptin in combating DIC-triggered kidney damage.