Sinapic acid attenuates colistin-driven nephrotoxicity by targeting the miRNA-21/SIRT1/NF-κB pathway and facilitating tubular repair and inflammation in a rat model

The present study aimed to investigate the nephrotoxic effects of colistin (CS) in a rat model and to elucidate the potential renoprotective mechanisms of sinapic acid (SA) at biochemical, molecular, and metabolic levels. Colistin administration induced pronounced renal dysfunction, as evidenced by significant elevations in serum creatinine (Scr) and blood urea nitrogen (BUN), along with marked increases in kidney injury biomarkers, including KIM-1, NGAL, FABP, IL-18, MCP-1, and YKL-40. Metabolic disruption was further confirmed by reduced ATP levels and increased lactate dehydrogenase (LDH) and triacylglycerol (TAG) concentrations, indicating mitochondrial dysfunction and cytotoxicity. Serum proteomic profiling using proximity extension assay identified significant alterations in 22 of 43 proteins, with IL-1β, IL-2, CXCL2, CSF-1, CCL22, and IFN-α2 showing marked upregulation following CS exposure. These inflammatory and immune-related proteins were significantly attenuated by SA co-treatment. Molecular analyses revealed that CS activated the miR-21/NF-κB/CD68 axis while suppressing SIRT1 expression, reflecting enhanced inflammation and macrophage infiltration. Sinapic acid effectively normalized these molecular disturbances. Furthermore, CS significantly upregulated renal mRNA expression of Cst3, Timp2, Igfbp7, Hgf, IL9, and Dkk3—genes associated with renal stress, fibrosis, and inflammation—whereas SA treatment markedly reduced their expression. Collectively, these findings demonstrate that sinapic acid exerts renoprotective effects primarily through modulation of inflammatory signaling pathways, suppression of miR-21/NF-κB-mediated responses, restoration of SIRT1 activity, and improvement of metabolic homeostasis. The study confirms the therapeutic potential of SA against colistin-induced nephrotoxicity.