CKD Increases Carbonylation of HDL and Is Associated with Impaired Antiaggregant Properties

Nans Florens (1, 2) , Catherine Calzada (1) , Sandrine Lemoine (1, 2) , Marie Michèle Boulet (1) , Nicolas Guillot (1) , Christophe Barba (1) , Julie Roux (1) , Fréderic Delolme (3) , Adeline Page (3) , Jean Michel Poux (4) , Maurice Laville (4) , Philippe Moulin (1, 5) , Laurent Soulère (6) , Fitsum Guebre Egziabher (1, 2) , Laurent Juillard (1, 2) , Christophe O Soulage (1)

1 CarMeN - Cardiovasculaire, métabolisme, diabétologie et nutrition
2 Department of Nephrology, Transplantation and Clinic Immunology [Hospices civils de Lyon]
3 SFR Biosciences
4 AURAL - Association pour l'Utilisation du Rein Artificiel Région Lyonnaise
5 Fédération d’Endocrinologie, Maladies Métaboliques, Diabète et Nutrition, Hôpital Louis Pradel
6 ICBMS - Institut de Chimie et Biochimie Moléculaires et Supramoléculaires

BACKGROUND: 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 in vitro. METHODS: 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 ex vivo assessment of the antiaggregant properties of HDL, we collected blood samples from 15 healthy volunteers, 25 patients on hemodialysis, and 20 on peritoneal dialysis. We analyzed malondialdehyde, 4-hydroxynonenal (HNE), and 4-hydroxy-2-hexenal protein adduct levels. Platelet aggregation and activation were assessed by aggregometry, thromboxane B2 assay, or FACS. We modified HDL from controls by incubating it overnight at 37°C with 100 µM of HNE. RESULTS: 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. CONCLUSIONS: 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.

Domaines: Sciences du Vivant [q-bio]

Nans Florens, Catherine Calzada, Sandrine Lemoine, Marie Michèle Boulet, Nicolas Guillot, et al.. CKD Increases Carbonylation of HDL and Is Associated with Impaired Antiaggregant Properties. Journal of the American Society of Nephrology, 2020, 31 (7), pp.1462-1477. ⟨10.1681/ASN.2019111205⟩. ⟨hal-03046430⟩