title: The cardiovascular effect of the uremic solute indole-3 acetic acid.
abstract: In CKD, uremic solutes may induce endothelial dysfunction, inflammation, and oxidative stress, leading to increased cardiovascular risk. We investigated whether the uremic solute indole-3 acetic acid (IAA) predicts clinical outcomes in patients with CKD and has prooxidant and proinflammatory effects. We studied 120 patients with CKD. During the median study period of 966 days, 29 patients died and 35 experienced a major cardiovascular event. Kaplan-Meier analysis revealed that mortality and cardiovascular events were significantly higher in the higher IAA group (IAA>3.73 µM) than in the lower IAA group (IAA<3.73 µM). Multivariate Cox regression analysis demonstrated that serum IAA was a significant predictor of mortality and cardiovascular events after adjustments for age and sex; cholesterol, systolic BP, and smoking; C-reactive protein, phosphate, body mass index, and albumin; diastolic BP and history of cardiovascular disease; and uremic toxins p-cresyl sulfate and indoxyl sulfate. Notably, IAA level remained predictive of mortality when adjusted for CKD stage. IAA levels were positively correlated with markers of inflammation and oxidative stress: C-reactive protein and malondialdehyde, respectively. In cultured human endothelial cells, IAA activated an inflammatory nongenomic aryl hydrocarbon receptor (AhR)/p38MAPK/NF-κB pathway that induced the proinflammatory enzyme cyclooxygenase-2. Additionally, IAA increased production of endothelial reactive oxygen species. In conclusion, serum IAA may be an independent predictor of mortality and cardiovascular events in patients with CKD. In vitro, IAA induces endothelial inflammation and oxidative stress and activates an inflammatory AhR/p38MAPK/NF-κB pathway.
authors.affiliation: Aix Marseille University, Inserm, UMR 1076, Marseille, France; laetitia.dou@univ-amu.fr.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Dou
authors.affiliation: Aix Marseille University, Inserm, UMR 1076, Marseille, France; Nephrology Dialysis Renal Transplantation Center, APHM, CHU Conception, Marseille, France;
authors.forename: Marion
authors.initials: M
authors.lastname: Sallée
authors.affiliation: Aix Marseille University, Inserm, UMR 1076, Marseille, France;
authors.forename: Claire
authors.initials: C
authors.lastname: Cerini
authors.affiliation: Aix Marseille University, Inserm, UMR 1076, Marseille, France;
authors.forename: Stéphane
authors.initials: S
authors.lastname: Poitevin
authors.affiliation: Aix Marseille University, Inserm, UMR 1076, Marseille, France; Nephrology Dialysis Renal Transplantation Center, APHM, CHU Conception, Marseille, France;
authors.forename: Bertrand
authors.initials: B
authors.lastname: Gondouin
authors.affiliation: Nephrology Dialysis Renal Transplantation Center, APHM, CHU Conception, Marseille, France;
authors.forename: Noemie
authors.initials: N
authors.lastname: Jourde-Chiche
authors.affiliation: Aix Marseille University, Inserm, UMR 1076, Marseille, France;
authors.forename: Karim
authors.initials: K
authors.lastname: Fallague
authors.affiliation: Aix Marseille University, Inserm, UMR 1076, Marseille, France; Nephrology Dialysis Renal Transplantation Center, APHM, CHU Conception, Marseille, France;
authors.forename: Philippe
authors.initials: P
authors.lastname: Brunet
authors.affiliation: Biochemistry Laboratory, Aix Marseille University, Marseille, France; and.
authors.forename: Raymond
authors.initials: R
authors.lastname: Calaf
authors.affiliation: Aix Marseille University, Inserm, UMR 1076, Marseille, France; Nephrology Dialysis Renal Transplantation Center, APHM, CHU Conception, Marseille, France;
authors.forename: Bertrand
authors.initials: B
authors.lastname: Dussol
authors.affiliation: Biochemistry Laboratory, APHM, CHU Timone, Marseille, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Mallet
authors.affiliation: Aix Marseille University, Inserm, UMR 1076, Marseille, France;
authors.forename: Françoise
authors.initials: F
authors.lastname: Dignat-George
authors.affiliation: Aix Marseille University, Inserm, UMR 1076, Marseille, France; Nephrology Dialysis Renal Transplantation Center, APHM, CHU Conception, Marseille, France;
authors.forename: Stephane
authors.initials: S
authors.lastname: Burtey
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002318:Cardiovascular Diseases / Q000097:blood* / Q000209:etiology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007210:Indoleacetic Acids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000150:complications / Q000401:mortality; D015398:Signal Transduction; D014511:Uremia / Q000150:complications; D055815:Young Adult
chemical_list: D007210:Indoleacetic Acids; D017382:Reactive Oxygen Species; C030737:indoleacetic acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
keywords: cardiovascular disease; chronic kidney disease; endothelial cells; uremia