Abstract 11472: Uremic Toxin Aggravates Atherosclerosis by Suppression of Endothelial Soluble Flt-1 Production in CKD
CKD related atherosclerosis relates to cardiovascular events in CKD patients and the mechanism is not fully elucidated. We already demonstrated that soluble Flt-1 (sFlt-1), which is the decoy receptor of PLGF (placental growth factor), is decreased in CKD patients and the PLGF/sFlt-1 ratio is correlated with the number of diseased coronary artery. 5/6 nephrectomised ApoE KO mice, which is the model of CKD related atherosclerosis, increased atherosclerotic lesion of thoracoabdominal aorta and aortic root more compared to ApoE KO mice and administration of recombinant sFlt-1 inhibit the progression of atherosclerosis, which means sFlt-1 is a key molecule to inhibit progression of atherosclerosis in CKD patients. However it is unknown which factor regulates sFlt-1 level in CKD patients. RT-PCR analysis showed that sFlt-1 mRNA is decreased in the lung and kidney of 5/6 nephlectomised ApoE KO mice, which is endothelial rich tissue. It indicates sFlt-1 is decreased not only in kidney, but in entire endothelial cells. To investigate if sFlt-1 is decreased in endothelial cells by endothelial dysfunction in CKD patients, we cultured human microvascular endothelial cells with serum from CKD patients or FBS with indoxyl sulphate, one of the uremic toxins, and revealed that sFlt-1 mRNA was decreased in both groups. Protein level of sFlt-1 was also decreased in endothelial cells with indoxyl sulphate compared to control. It indicates that indoxyl sulphate can be a regulator of sFlt-1 production in CKD patients. Cultivation of endothelial cells with serum of CKD patients revealed that markers of endothelial dysfunction (selectin, ICAM1, and VCAM1) were increased by RT-PCR. Markers of oxidative stress (HO-1 and NOX-2) and ROS were increased in endothelial cells treated with serum from CKD patients and FBS with indoxyl sulphate by RT-PCR analysis, respectively. These results demonstrate that sFlt-1 production in endothelial cells is suppressed by uremic toxins, like indoxyl sulphate, through endothelial damage by oxidative stress in renal dysfunction, which results in progression of atherosclerosis in CKD patients.
- © 2013 by American Heart Association, Inc.