Ranolazine is associated with attenuation of lipopolysaccharide-induced acute kidney injury via modulation of inflammatory, oxidative, and vascular markers.

Sepsis triggers acute kidney injury (AKI) through inflammatory, oxidative, apoptotic, and microvascular mechanisms. This study investigated the renoprotective effects of ranolazine (RAN) in a lipopolysaccharide (LPS)-induced AKI model. Thirty-two male Wistar albino rats were allocated to four groups: Control, LPS (5 mg/kg, intraperitoneal), LPS + RAN (100 mg/kg orally, twice daily for three days), and RAN. Six hours after LPS administration, kidney tissues were collected for histopathological and immunohistochemical analysis of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor alpha (TNF-α), and caspase 3 (Cas-3). Biochemical assessments included total antioxidant status (TAS), total oxidative status (TOS), oxidative stress index (OSI), and serum blood urea nitrogen (BUN) and creatinine levels. Gene expression of interleukin-1 beta (IL-1β), sirtuin 1 (SIRT-1), heme oxygenase-1 (HO-1), hypoxia-inducible factor-1 alpha (HIF-1α), vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), fms-related tyrosine kinase-1 (FLT-1), and aquaporin 2 (AQP-2), sodium channel epithelial 1 alpha subunit (SCNN1A), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM1) was analyzed. LPS induced renal injury, evidenced by increased NF-κB, TNF-α, Cas-3, TOS, OSI, BUN, creatinine, and FLT-1, SCNN1A, NGAL, and KIM1 expression, together with decreased TAS, SIRT-1, HO-1, HIF-1α, VEGF, and AQP-2. RAN treatment significantly attenuated these alterations, reducing inflammation, oxidative stress, and apoptosis, tubular injury and tubular transport-related signaling while partially restoring vascular and hypoxia-related signaling. Prophylactic RAN attenuated inflammation, oxidative stress, and tubular injury while preserving renal function and modulating vascular and tubular pathways in sepsis-associated AKI, supporting its potential as an adjunctive therapeutic strategy.