Imidazole Propionate Induces Kidney Damage by Activating the ROS-NLRP3 Signaling Pathway Through mTOR Inhibition of Autophagy in Renal Tubular Epithelial Cells.

L-Histidine, a parent structure of environmental contaminants (e.g., pesticides and preservatives), may undergo bioaccumulation through the food chain and be metabolized by the gut microbiota into deleterious compounds, ultimately compromising human health. Recent studies have identified abnormally elevated levels of the histidine-derived metabolite imidazole propionate (ImP) in the serum of type 2 diabetes mellitus patients. However, the pathophysiological implications of excessive ImP on renal function and its underlying molecular mechanisms remain poorly characterized. This study is the first to elucidate the detrimental effects of ImP on renal function in mice and its molecular mechanisms. Our findings demonstrate that ImP exacerbates renal dysfunction and induces structural and functional abnormalities in renal tubules. Mechanistically, ImP significantly suppresses autophagy in renal tubular epithelial cells and activates the reactive oxygen species (ROS)-NOD-like receptor pyrin domain-containing 3 (NLRP3) signaling pathway, thereby promoting the expression of the pro-inflammatory cytokine interleukin-1β (IL-1β). Notably, the mechanistic target of rapamycin (mTOR) inhibitor rapamycin (Rap) restores autophagy, inhibits the ROS/NLRP3/IL-1β axis, and mitigates ImP-induced renal injury. Transcriptomic sequencing of mouse kidneys reveals that ImP upregulates the expression of autophagy- and inflammation-related genes, while its inhibitor suppresses these genetic alterations. This study highlights the potential nephrotoxic effects of ImP and underscores the therapeutic value of Rap, providing a theoretical foundation for understanding the role of gut microbiota metabolites in the pathogenesis, prevention, and treatment of kidney diseases.