Alpha-lipoamide prevents acute kidney injury in mouse by inhibiting renal tubular epithelial cell pyroptosis.

Acute kidney injury (AKI) is a critical condition marked by a sudden decline in kidney function, frequently resulting in high morbidity and mortality. Renal ischemia-reperfusion injury (IRI) is a leading cause of AKI, characterized by reactive oxygen species (ROS) release, cell death, and inflammation. Alpha-lipoamide (ALM), a neutral derivative of lipoic acid, is recognized for its antioxidant and organ-protective properties. Prior research indicates that ALM mitigates diabetic nephropathy by decreasing ROS. This study examines ALM's protective role in a mouse model of IRI-induced AKI and its mechanisms using mouse renal tubular epithelial cells (mRTECs). Mice were subjected to IRI by renal artery occlusion for 30 min, followed by reperfusion, and treated with ALM (100 or 200 mg/kg) for three days before surgery. In vitro, mRTECs were exposed to hypoxia/reoxygenation injury, with ALM (200 μM) applied to assess oxidative stress. ALM significantly decreased serum creatinine levels, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury marker-1 (KIM-1), mitigated kidney injury, and reduced both ROS and Malondialdehyde(MDA) content. ALM increased glutathione (GSH) levels and upregulated SIRT1 expression. This resulted in the deacetylation of the NF-κB p65 subunit, facilitating its nuclear export, suppressing NF-κB signaling, and reducing the expression of the inflammatory marker NLRP3. ALM decreased the levels of pyroptosis-related proteins (Caspase-1, GSDMD, and IL-1β), which in turn suppressed IL-6 secretion and macrophage infiltration. These findings suggest that ALM reduces inflammation and pyroptosis-associated proteins by promoting the upregulation of SIRT1, ultimately preventing IRI-mediated renal tubular epithelial cell damage and inflammation.