Patients with chronic kidney disease (CKD) and end stage renal disease suffer from increased cardiovascular events and cardiac mortality. Prior studies have demonstrated a portion of this enhanced risk can be attributed to the accumulation of microbiota-derived toxic metabolites, with most studies focusing on the sulfonated form of p-cresol (PCS). However, unconjugated p-cresol (uPC) itself was never assessed due to rapid and extensive first pass metabolism that results in negligible serum concentrations of uPC.These reports thus failed to consider the host exposure to uPC prior to hepatic metabolism. In the current study, we not only measured the impact of altering the intestinal microbiota on lipid accumulation in coronary arteries, but also examined macrophage lipid uptake and handling pathways in response to uPC.We found atherosclerotic-prone mice fed a high fat diet exhibited significantly higher coronary artery lipid deposits upon receiving fecal material from CKD mice. Furthermore, treatment with uPC increased total cholesterol, triglycerides, hepatic, and aortic fatty deposits in non-CKD mice. Studies employing an in vitro macrophage model demonstrated uPC exposure increased apoptosis where PCS did not. Additionally, uPC exhibited higher potency than PCS to stimulate low density lipoprotein (LDL) uptake and only uPC induced endocytosis and pinocytosis-related genes. Pharmacological inhibition of varying cholesterol influx and efflux systems indicated that uPC increased macrophage LDL uptake by activating macropinocytosis.Overall, these findings indicate uPC itself has a distinct impact on macrophage biology that may contribute to increased cardiovascular risk in patients with CKD.
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