4-hydroxy-2-hexenal and Renal-Insufficiency--Chronic

CKD is associated with increased oxidative stress that correlates with occurrence of cardiovascular events. Modifications induced by increased oxidative stress particularly affect circulating lipoproteins such as HDL that exhibit antiatheromatous and antithrombotic properties. To explore the specific role of oxidative modifications of HDL in CKD and their effect on the platelet-targeting antiaggregant properties of HDL, we used a CKD (5/6 nephrectomy) rabbit model. For. HDL from CKD rabbits and patients on hemodialysis had HNE adducts. The percentage of platelet aggregation or activation induced by collagen was significantly higher when platelets were incubated with HDL from CKD rabbit and hemodialysis groups than with HDL from the control group. In both rabbits and humans, platelet aggregation and activation were significantly higher in the presence of HNE-modified HDL than with HDL from their respective controls. Incubation of platelets with a blocking antibody directed against CD36 or with a pharmacologic inhibitor of SRC kinases restored the antiaggregative phenotype in the presence of HDL from CKD rabbits, patients on hemodialysis and peritoneal dialysis, and HNE-modified HDL.. HDL from CKD rabbits and patients on hemodialysis exhibited an impaired ability to inhibit platelet aggregation, suggesting that altered HDL properties may contribute to the increased cardiovascular risk in this population.

Topics: Adult; Aged; Aged, 80 and over; Aldehydes; Animals; Antibodies; Blood Platelets; CD36 Antigens; Cells, Cultured; Disease Models, Animal; Female; Humans; JNK Mitogen-Activated Protein Kinases; Lipoproteins, HDL; Male; Malondialdehyde; Middle Aged; Oxidation-Reduction; Oxidative Stress; Peritoneal Dialysis; Phosphorylation; Platelet Aggregation; Protein Carbonylation; Protein Kinase Inhibitors; Rabbits; Renal Insufficiency, Chronic; src-Family Kinases

Lipid aldehydes originating from the peroxidation of n-3 and n-6 polyunsaturated fatty acids are increased in hemodialysis (HD) patients, a process already known to promote oxidative stress. However, data are lacking for patients with chronic kidney disease (CKD) before the initiation of HD. We prospectively evaluated the changes of plasma concentrations of two major lipid aldehydes, 4-HHE and 4-HNE, according to the decrease of glomerular filtration rate (GFR) in 40 CKD and 13 non-CKD participants. GFR was measured by inulin or iohexol clearance. Thus, 4-hydroxy-2-nonenal (4-HNE) and 4-hydroxy-2-hexenal (4-HHE) were quantitated in plasma by gas chromatography coupled with mass spectrometry and their covalent adducts on proteins were quantified by immunoblotting. On the one hand, 4-HHE plasma concentration increased from CKD stage I-II to CKD stage IV-V compared to non-CKD patients (4.5-fold higher in CKD IV-V,

Topics: Adult; Aged; Aldehydes; Biomarkers; Case-Control Studies; Female; Gas Chromatography-Mass Spectrometry; Glomerular Filtration Rate; Humans; Kidney; Lipid Peroxidation; Male; Middle Aged; Oxidative Stress; Renal Insufficiency, Chronic; Up-Regulation