Zingerone alleviates diabetic nephropathy by interrupting the ER stress-inflammation-apoptosis cascade in streptozotocin-induced diabetic mice.

Endoplasmic reticulum (ER) stress plays a critical role in the pathogenesis of diabetic nephropathy. In this study, we aimed to investigate the protective effects of zingerone on the kidney and elucidate the underlying mechanisms in streptozotocin (STZ)-induced diabetic mice. Diabetic mice were randomly assigned to three groups: untreated control, diabetic control, and STZ+zingerone-treated group. Over a 3-month period, we monitored body weight, blood glucose (BG), blood urea nitrogen (BUN), serum creatinine (SCR), 24-h urinary protein (UP) excretion levels, and 24-h urinary volume (UV). Renal injury, apoptosis, inflammation, and ER stress were evaluated using histopathology, TUNEL staining, reverse transcription polymerase chain reaction (RT-PCR), western blotting, and immunofluorescence. In vitro, mouse glomerular mesangial cells were exposed to high glucose, with or without zingerone or the ER stress inhibitor phenylbutyric acid (PBA). Thereafter, the expression levels of ER stress markers (CHOP and GRP78), inflammatory factors (NF-κB and TGF-β1), and apoptotic indices were assessed. Diabetic mice exhibited significantly elevated BG, BUN, SCR, 24-h UP, and ER stress marker levels, along with increased 24-h UV, renal apoptosis, and inflammation. Zingerone treatment significantly mitigated these parameters and improved renal pathological manifestations. In vitro, both zingerone and PBA effectively suppressed high glucose-induced ER stress, inflammation, and apoptosis in mesangial cells. These findings demonstrated that zingerone attenuated diabetic renal injury through inhibition of ER stress-related pathways and downstream inflammation, thereby underscoring its potential as a therapeutic candidate for diabetic nephropathy.