Nesfatin-1 mitigates calcium oxalate nephropathy in mice by modulating GPR12 and inhibiting PKCα/NADPH oxidase.

Nephrolithiasis, or kidney stone disease, is a prevalent and recurring condition characterized by significant oxidative stress, inflammation, apoptosis, necroptosis, and fibrosis. Current therapeutic strategies often fall short in preventing recurrence or fully addressing the complex pathological changes. Nesfatin-1, a bioactive peptide, is recognized for its antioxidant, anti-inflammatory, and antifibrotic properties. However, its specific role in nephrolithiasis-associated pathologies and the receptor mediating its protective effects have remained largely unexplored, representing a critical knowledge gap this study addresses.

Researchers induced a mouse model of nephrolithiasis via glyoxylate administration to simulate kidney stone formation, and used calcium oxalate monohydrate (COM) to create in vitro tubular epithelial cell injury models. They assessed kidney function, histopathology, oxidative stress, inflammation, apoptosis, and renal interstitial fibrosis using various assay kits, confocal microscopy, and protein/mRNA expression analysis. To identify the receptor and elucidate the molecular mechanism, co-immunoprecipitation was performed. Nesfatin-1 was administered, though specific dosing details were not provided in the abstract, to evaluate its protective effects.

Mice with nephrolithiasis exhibited significantly reduced endogenous nesfatin-1 expression, alongside elevated markers of kidney damage, including histological abnormalities, inflammation, necroptosis, and fibrosis. The study found that nesfatin-1 effectively mitigated these pathological changes. Mechanistically, nesfatin-1 demonstrated a crucial role in modulating GPR12 receptor oligomerization. This modulation led to the inhibition of the COM-induced PKCα/NADPH oxidase pathway, a key driver of oxidative stress and inflammation in kidney injury. This suggests a direct link between nesfatin-1, GPR12 signaling, and the suppression of detrimental oxidative processes. The findings highlight a novel pathway through which nesfatin-1 exerts its protective actions.

Nesfatin-1 modulated GPR12 oligomerization and inhibited the COM-induced PKCα/NADPH oxidase pathway via modulation of GPR12 receptor signaling.