title: Endothelial dysfunction and oxidative stress in polycystic kidney disease.
abstract: Cardiovascular disease (CVD) is the leading cause of premature mortality in ADPKD patients. The aim was to identify potential serum biomarkers associated with the severity of ADPKD. Serum samples from a homogenous group of 61 HALT study A ADPKD patients [early disease group with estimated glomerular filtration rate (eGFR) >60 ml·min(-1)·1.73 m(-2)] were compared with samples from 49 patients from the HALT study B group with moderately advanced disease (eGFR 25-60 ml·min(-1)·1.73 m(-2)). Targeted tandem-mass spectrometry analysis of markers of endothelial dysfunction and oxidative stress was performed and correlated with eGFR and total kidney volume normalized to the body surface area (TKV/BSA). ADPKD patients with eGFR >60 ml·min(-1)·1.73 m(-2) showed higher levels of CVD risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA), homocysteine, and S-adenosylhomocysteine (SAH) compared with the healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, SDMA, homocysteine, and SAH remained negatively correlated with eGFR. Resulting cellular methylation power [S-adenosylmethionine (SAM)/SAH ratio] correlated with the reduction of renal function and increase in TKV. Concentrations of prostaglandins (PGs), including oxidative stress marker 8-isoprostane, as well as PGF2α, PGD₂, and PGE₂, were markedly elevated in patients with ADPKD compared with healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, increased PGD₂ and PGF₂α were associated with reduced eGFR, whereas 8-isoprostane and again PGF₂α were associated with an increase in TKV/BSA. Endothelial dysfunction and oxidative stress are evident early in ADPKD patients, even in those with preserved kidney function. The identified pathways may provide potential therapeutic targets for slowing down the disease progression.
authors.affiliation: Department of Anesthesiology, University of Colorado, Aurora, Colorado; Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado; and Jelena.Klawitter@ucdenver.edu.
authors.forename: Jelena
authors.initials: J
authors.lastname: Klawitter
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado; and.
authors.forename: Berenice Y
authors.initials: BY
authors.lastname: Reed-Gitomer
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado; and.
authors.forename: Kim
authors.initials: K
authors.lastname: McFann
authors.affiliation: Department of Anesthesiology, University of Colorado, Aurora, Colorado;
authors.forename: Alexander
authors.initials: A
authors.lastname: Pennington
authors.affiliation: Department of Anesthesiology, University of Colorado, Aurora, Colorado;
authors.forename: Jost
authors.initials: J
authors.lastname: Klawitter
authors.affiliation: Division of General Internal Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Kaleab Z
authors.initials: KZ
authors.lastname: Abebe
authors.affiliation: Department of Anesthesiology, University of Colorado, Aurora, Colorado;
authors.forename: Jacek
authors.initials: J
authors.lastname: Klepacki
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado; and.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Cadnapaphornchai
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado; and.
authors.forename: Godela
authors.initials: G
authors.lastname: Brosnahan
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado; and.
authors.forename: Michel
authors.initials: M
authors.lastname: Chonchol
authors.affiliation: Department of Anesthesiology, University of Colorado, Aurora, Colorado;
authors.forename: Uwe
authors.initials: U
authors.lastname: Christians
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado; and.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Schrier
mesh_terms: D000293:Adolescent; D000328:Adult; D004727:Endothelium / Q000473:pathology*; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007668:Kidney / Q000473:pathology; D008297:Male; D009569:Nitric Oxide / Q000502:physiology; D018384:Oxidative Stress; D016891:Polycystic Kidney, Autosomal Dominant / Q000378:metabolism / Q000473:pathology*; D011453:Prostaglandins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D055815:Young Adult
chemical_list: D011453:Prostaglandins; D009569:Nitric Oxide
keywords: ADPKD; NO pathway; biomarkers; endothelial dysfunction; oxidative stress