Abstract 15923: Indoxyl Sulfate Increases Ly6Chigh Inflammatory Monocytes and Enhanced Neointima Formation in Response to Vessel Injury
[Background] Chronic kidney disease (CKD) is an independent risk factor for cardiovascular disease. Indoxyl sulfate, a uremic toxin, is associated with vascular disease and mortality in CKD patients. Ly6Chigh inflammatory monocytes are preferentially recruited to atherosclerotic plaques. Thus we hypothesized that indoxyl sulfate enhances atherosclerosis through increasing the inflammatory monocytes.
[Methods] Eight weeks old male C57BL/6j mice were administrated 0.1 % (w/v) indoxyl sulfate in drinking water or only water. Four weeks after, polyethylene cuff was placed around the right femoral artery for two weeks to induce intimal thickening. Sections cut from femoral artery were examined by staining Elastica-Van-Gieson for morphometric analysis, as well as immunohistochemistry. Leukocytes were stained for CD45, CD115, Ly6C, P-selectin glycoligand-1 (PSGL-1) and CCR-2 followed by performing flow cytometry. Monocytes were determined by double positive for CD45 and CD115.
[Results] The extent of cuff-induced intimal thickening of the femoral artery was much greater in mice treated with indoxyl sulfate (IS+Cuff) when compared to control (Cuff) mice (p < 0.05). In neoitima, both MOMA-2 and alpha-smooth muscle actin positive cells were existed in Cuff and IS+Cuff groups, however, Ly6C positive cells were recruited only in IS+Cuff group. Flow cytometric analysis of peripheral blood monocytes showed that indoxyl sulfate significantly increased the number of Ly6Chigh monocytes, and enhanced expression level of PSGL-1 and CCR-2. In bone marrow, indoxyl sulfate increased CCR-2 expression, but did not alter the number of monocyte precursor cells expressed Ly6C. In spleen, Indoxyl sulfate did not affect the number and CCR-2 expression in Ly6Chigh monocytes. Real-time quantitative PCR analysis showed that indoxyl sulfate also enhanced endothelial adhesion molecules such as E-selectin.
[Conclusion] Indoxyl sulfate, a uremic toxin, enhanced cuff-injured neointima formation by increasing Ly6Chigh inflammatory monocytes presumably via CCR-2 dependent pathway and by activating endothelium. These findings reveal novel role for indoxyl sulfate on inflammatory state in patients with CKD.
- © 2012 by American Heart Association, Inc.