Acute kidney injury (AKI) is a common complication associated with sepsis, yet no effective treatment is currently available. The primary mechanisms involved in lipopolysaccharide (LPS)-induced septic AKI are oxidative stress, inflammation, and apoptosis. This study aimed to investigate the potential renoprotective effects of linagliptin, an antidiabetic dipeptidyl peptidase (DPP)-4 inhibitor, against LPS-induced AKI with special emphasis on renal brain-derived neurotrophic factor (BDNF)/nuclear factor erythroid 2-related factor 2 (NRF2) axis. Mice were divided into control, LPS, LPS + linagliptin, and LPS + linagliptin+ANA-12 (tropomyosin receptor kinase B (TrkB) antagonist) groups. Our results revealed that linagliptin, partially through BDNF augmentation, ameliorated AKI, evidenced by the improved histological structure and function of the kidney where serum creatinine, blood urea nitrogen, cystatin C, and renal kidney injury molecule-1were decreased with increased serum albumin. These improvements result from glucagon-like peptide-1/BDNF/TrkB-mediated NRF2 activation, enhancing antioxidant, anti-inflammatory, and antiapoptotic pathways. Linagliptin, through NRF2 augmentation, suppressed renal myeloperoxidase, malondialdehyde, NLR Family pyrin domain-containing 3 inflammasome, nuclear factor-kappaB, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, B-cell lymphoma 2 (Bcl2)-associated X protein, while boosting the antioxidant glutathione and the antiapoptotic Bcl2 contents. The administration of ANA-12 before linagliptin partially reversed these beneficial effects. Accordingly, our results suggest that linagliptin has therapeutic potential in managing LPS-induced AKI. Furthermore, they provide insights into its underlying mechanisms, highlighting renal BDNF signaling as a potential therapeutic target through downstream NRF2 enhancement and its associated antioxidant, anti-inflammatory, and antiapoptotic effects.
