Nesfatin-1 mitigates calcium oxalate nephropathy in mice through GPR12 receptor modulation and PKCα/NADPH oxidase pathway inhibition.

AIMS: Nephrolithiasis, a prevalent and recurring kidney disease is associated with oxidative stress, inflammation, apoptosis, necroptosis, and fibrosis. Nesfatin-1, a bioactive peptide, is known to have antioxidant, anti-inflammatory, and antifibrotic properties, however, its role in nephrolithiasis associated pathological changes remains unexplored. Moreover, the receptor by which nesfatin-1 exerts its protective effects is unknown. Thus, the present study aimed to elucidate the role and underlying molecular mechanisms of nesfatin-1 in a mouse model of glyoxylate-induced nephrolithiasis/nephrocalcinosis.

MATERIALS AND

METHODS

Mouse model of nephrolithiasis was created via administration of glyoxylate, and cell injury models of tubular epithelial cells were done using calcium oxalate monohydrate (COM). Kidney function, histopathology, oxidative stress, inflammation, apoptosis, and renal interstitial fibrosis were measured using assay kits, confocal microscopy and protein/mRNA expression analysis. Moreover, co-immunoprecipitation was performed to investigate the receptors involved and underlying molecular mechanism.

KEY FINDINGS: Nephrolithiasis mice showed reduced nesfatin-1 expression and elevated markers of kidney damage, including, histological abnormalities, inflammation, necroptosis, and fibrosis. Mechanistically, nesfatin-1 modulated the GPR 12 oligomerization and inhibited the COM-induced PKCα/NADPH oxidase pathway via modulation of GPR 12 receptor signaling.

SIGNIFICANCE: This study is the first to report that nesfatin-1 may be a potential therapeutic agent for nephrocalcinosis/nephrolithiasis via modulation of GPR12 receptor signaling pathway. This study also highlights nesfatin-1's protective role against kidney stone formation and related tubular injury by suppressing the oxidative PKCα/NADPH oxidase pathway.