Trigonelline attenuated sepsis-induced acute kidney injury by activating NAD+/SIRT1 Pathway

Sepsis-induced acute kidney injury (SAKI) is one of the most frequent complications in patients with sepsis and is strongly associated with poor clinical outcomes. Trigonelline (TRL), a bioactive pyridine alkaloid isolated from fenugreek, has exhibited therapeutic effects on various diseases. This study aimed to investigate the effects of TRL on SAKI and whether TRL exerted its function via NAD+/SIRT1 pathway activation. A single dose (10 mg/kg body weight) of lipopolysaccharide (LPS) was intraperitoneally administered to establish a mouse SAKI model. After 24 h, compared with the control group, the plasma levels of kidney function indicators creatinine and blood urea nitrogen, oxidative stress indicators hydrogen peroxide and malondialdehyde, and inflammatory factors tumor necrosis factor-alpha and interleukin-1beta were significantly increased. Meanwhile, hematoxylin and eosin staining results revealed that LPS treatment caused glomerular structure disruption, renal tubular luminal narrowing, and renal tubular structure deterioration. TRL treatment significantly reduced the plasma kidney function indicators, oxidative stress, and inflammatory factors levels in the SAKI mice, accompanied by improvements in the renal pathological changes. Furthermore, TRL treatment increased the NAD+ levels, upregulated the SIRT1 expression, and downregulated the NOX4 expression in the kidney of the SAKI mice. Subsequently, EX-527, a selective SIRT1 inhibitor, was used for inhibiting SIRT1, and it reversed the protective effect of TRL in SAKI. Our results revealed that TRL improved renal function and alleviated inflammation and oxidative stress in SAKI mice by NAD+/SIRT1 pathway activation. Therefore, TRL may be a potential therapeutic approach for SAKI treatment. Key words Trigonelline " Sepsis-induced acute kidney injury " NAD+ " SIRT1.