Blood Levels of Endocannabinoids, Oxylipins, and Metabolites Are Altered in Hemodialysis Patients

Bruce A Watkins; Allon N Friedman; Jeffrey Kim; Kamil Borkowski; Shaun Kaiser; Oliver Fiehn; John W Newman

doi:10.3390/ijms23179781

Blood Levels of Endocannabinoids, Oxylipins, and Metabolites Are Altered in Hemodialysis Patients

Int J Mol Sci. 2022 Aug 29;23(17):9781. doi: 10.3390/ijms23179781.

Authors

Bruce A Watkins¹, Allon N Friedman², Jeffrey Kim³, Kamil Borkowski⁴, Shaun Kaiser⁵, Oliver Fiehn⁶, John W Newman⁷

Affiliations

¹ Department of Nutrition, University of California, Davis, CA 95616, USA.
² University Hospital, Suite 6100, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
³ Department of Internal Medicine, University of California, Davis, CA 95616, USA.
⁴ West Coast Metabolomics Center, Genome Center, University of California, Davis, CA 95616, USA.
⁵ Texas Kidney Institute, Dallas, TX 75230, USA.
⁶ West Coast Metabolomics Center, University of California, Davis, CA 95616, USA.
⁷ Obesity and Metabolism Research Unit, USDA-ARS Agriculture Research Service, Davis, CA 95616, USA.

Abstract

Hemodialysis patients (HDPs) have higher blood pressure, higher levels of inflammation, a higher risk of cardiovascular disease, and unusually low plasma n-3 polyunsaturated fatty acid (PUFA) levels compared to healthy subjects. The objective of our investigation was to examine the levels of endocannabinoids (eCBs) and oxylipins (OxLs) in female HDPs compared to healthy matched female controls, with the underlying hypothesis that differences in specific PUFA levels in hemodialysis patients would result in changes in eCBs and OxLs. Plasma phospholipid fatty acids were analyzed by gas chromatography. Plasma was extracted and analyzed using ultra-performance liquid chromatography followed by electrospray ionization and tandem MS for eCBs and OxLs. The global untargeted metabolite profiling of plasma was performed by GCTOF MS. Compared to the controls, HDPs showed lower levels of plasma EPA and the associated OxL metabolites 5- and 12-HEPE, 14,15-DiHETE, as well as DHA derived 19(20)-EpDPE. Meanwhile, no changes in arachidonylethanolamide or 2-arachidonylglycerol in the open circulation were detected. Higher levels of multiple N-acylethanolamides, monoacylglycerols, biomarkers of progressive kidney disease, the nitric oxide metabolism-linked citrulline, and the uremic toxins kynurenine and creatine were observed in HDP. These metabolic differences in cCBs and OxLs help explain the severe inflammatory and cardiovascular disease manifested by HDPs, and they should be explored in future studies.

Keywords: endocannabinoids; global metabolites; hemodialysis patient; oxylipins; polyunsaturated fatty acids; women.

MeSH terms

Cardiovascular Diseases* / etiology
Endocannabinoids
Fatty Acids
Fatty Acids, Omega-3*
Fatty Acids, Unsaturated
Female
Humans
Oxylipins
Renal Dialysis

Substances

Endocannabinoids
Fatty Acids
Fatty Acids, Omega-3
Fatty Acids, Unsaturated
Oxylipins

Grants and funding

This research was supported by funding provided to B.A.W. and the metabolomics effort at the University of Connecticut Health Center, Center on Aging. Additional support was provided by the USDA, Intramural Projects 5306-51530-019-00D, 5306-51530-022-00D, and 5306-51530-025-00D, and the West Coast Metabolomics Center, Grant NIH U24 DK097154. The USDA is an equal-opportunity provider and employer.