Linoelaidic acid alleviates COM-induced kidney injury and crystal deposition via the PPARγ/MAPK signaling pathway.

Renal injury and calcium oxalate crystal deposition are the core pathological processes of kidney stone formation, and their molecular mechanisms have not been fully elucidated while the clinical intervention methods are limited. Many studies have shown that the intestinal microbiota can produce various metabolites that affect renal function through the gut-kidney axis and participate in the formation of kidney stones. This study aims to identify the microbial metabolites related to kidney stone patients and explore their mechanism of action in kidney stones. Microbiome and metabolome analyses are used to search for microbial-related metabolites in the intestines of kidney stone patients. Using COM crystal-treated TCMK-1 cells as a model, the functions of metabolites are evaluated by detecting cell viability, apoptosis rate, cell-crystal adhesion, reactive oxygen species and MDA levels in vitro. In vivo, a glyoxylate-based kidney stone mouse model is established, and the effects of metabolites on renal function are assessed by HE staining, PAS staining, creatinine and urea nitrogen levels. The effects of metabolites on renal injury and crystal deposition are evaluated by Tunel, Von-Kossa staining, CD44 and OPN level detection. Transcriptional sequencing combined with western blot is used to search and verify the related signaling pathways affected by metabolites. It is found that linoelaidic acid is significantly decreased in kidney stone patients. Supplementing linoelaidic acid in vitro can significantly reduce COM crystal-induced cell apoptosis, crystal adhesion, ROS and MDA levels, and increase cell viability. In kidney stone mice, supplementing linoelaidic acid reduces renal tubular damage, crystal deposition, and improves renal function. Mechanistically, linoelaidic acid upregulates the expression of PPARγ in kidney stones to inhibit the activation of the MAPK signaling pathway. Linoelaidic acid can alleviate renal injury, oxidative stress and crystal deposition by regulating the PPARγ/MAPK signaling pathway, and may be a useful strategy for the treatment of kidney stones.