Effects of hemodialysis on plasma oxylipins

Abstract

Chronic kidney disease (CKD) is an important risk factor for cardiovascular and all-cause mortality. Survival rates among end-stage renal disease (ESRD) hemodialysis patients are poor and most deaths are related to cardiovascular disease. Oxylipins constitute a family of oxygenated natural products, formed from fatty acid by pathways involving at least one step of dioxygen-dependent oxidation. They are derived from polyunsaturated fatty acids (PUFAs) by cyclooxygenase (COX) enzymes, by lipoxygenases (LOX) enzymes, or by cytochrome P450 epoxygenase. Oxylipins have physiological significance and some could be of regulatory importance. The effects of decreased renal function and dialysis treatment on oxylipin metabolism are unknown. We studied 15 healthy persons and 15 CKD patients undergoing regular hemodialysis treatments and measured oxylipins (HPLC-MS lipidomics) derived from cytochrome P450 (CYP) monooxygenase and lipoxygenase (LOX)/CYP ω/(ω-1)-hydroxylase pathways in circulating blood. We found that all four subclasses of CYP epoxy metabolites were increased after the dialysis treatment. Rather than resulting from altered soluble epoxide hydrolase (sEH) activity, the oxylipins were released and accumulated in the circulation. Furthermore, hemodialysis did not change the majority of LOX/CYP ω/(ω-1)-hydroxylase metabolites. Our data support the idea that oxylipin profiles discriminate ESRD patients from normal controls and are influenced by renal replacement therapies.

Keywords: dialysis; eicosanoids; fatty acids; lipidomics; oxylipins.

Figure 1

Cytochrome P450 epoxygenase (CYP) and 12‐ and 15‐lipoxygenase (LOX)/ CYP (omega‐1)‐hydroxylase pathways evaluated in response hemodialysis. Linoleic (LA), arachidonic (AA), eicosapentaenoic (EPA), and docosahexaenoic acids (DHA) are converted to epoxyoctadecenoic acids (EpOMEs, e.g., 12,13‐EpOME), epoxyeicosatrienoic acid (EETs), epoxyeicosatetraenoic acids (EEQs), and epoxydocosapentaenoic acids (EDPs) by CYP epoxygenase, respectively. EpOMEs, EETs, EEQs, and EDPs primary metabolic fate is conversion to dihydroxyctadecenoic acids (DiHOMEs, e.g., 12, 13‐DiHOME), dihydroxyeicosatrienoic acids (DHETs, e.g., 5,6‐DHET), dihydroxyeicosatetraenoic acids (DiHETEs, e.g., 5,6‐DiHETE, 17,18‐DiHETE) and dihydroxydocosapentaenoic acids (DiHDPAs, 19, 20‐DiHDPA), respectively, by the soluble epoxide hydrolase (sEH) enzyme. LA, AA, EPA, and DHA are converted to hydroperoxylinoleic acids (HpODEs), hydroxyoctadecadienoic acids (HODEs), leukotriene B (LTB), lipoxin A (LXA), hydroxydocosahexaenoic acids (HDHAs), hydroperoxyeicosatetraenoic acids (HPETEs), and hydroxyeicosatetraenoic acids (HETEs) by LOX, CYP omega/(omega‐1)‐hydroxylase and peroxidase pathways. The metabolites measured within these pathways track the changes observed in LA, AA, EPA, and DHA, respectively