Abstract 18317: Abnormal High Density Lipoprotein (HDL) from Patients with Chronic Kidney Disease (CKD) Increases Arterial Blood Pressure: Role of Toll-Like Receptor-2 (TLR-2)

Background Patients with chronic kidney disease (CKD) exhibit a high cardiovascular morbidity and mortality, even in the early stages, and frequently develop hypertension. , Patients with advanced CKD have an uremic dyslipidemia, characterized by low levels of total cholesterol, low density lipoprotein and HDL cholesterol and elevated levels of triglycerides. In addition to its role in reverse cholesterol transport, HDL from healthy subjects (HS) exerts several potential vasoprotective effects. Thus, we compared endothelial effects of HDL from CKD patients and HS and potential consequences for blood pressure responses. Methods HDL was isolated from patients with CKD (K/DOQI stadium II, IV, V, each n=15) and healthy subjects (n=15) by sequential ultracentrifugation. The effect of HDL on endothelial nitric oxide production (NO) was assessed by electron spin resonance (ESR) spectroscopy. To evaluate the effects of HDL on systolic blood pressure (SBP) in vivo, HDL was injected into wild type and eNOS-deficient mice. Expression of VCAM-1 and endothelial mononuclear cell (MNC) adhesion was assessed. Moreover, endothelial repair capacity of HDL was assessed in vitro and vivo, using a gap closure assay and carotid injury model in nude mice . Results HDL from HS stimulated endothelial NO production; whereas HDL from CKD patients markedly inhibited the endothelial NO production (-80 % by HDL of these patients; P<0.05), even in incipient CKD. TLR2, but not TLR4 inhibition, prevented the inhibitory effects of HDLCKD on endothelial NO production. In vivo, CKD-HDL induced an increase of SBP (+10.7±1.1 mmHg; P<0.05), while healthy HDL reduced SBP (-11.3±1.7, P<0.05). Notably, HDL from patients with CKD induced endothelial VCAM-1 expression and promoted endothelial MNC adhesion, while HDL from healthy subjects did not. In vitro gap closure and in vivo reendothelialization after carotid injury were suppressed by HDL of CKD patients. Conclusion Our data demonstrate for the first time that endothelial-protective effects of HDL are considerably impaired in patients with CKD independently of the severity of CKD. Furthermore, HDL may be involved in initiation and aggravation of hypertension in these patients.