The uremic toxin hippurate promotes endothelial dysfunction via the activation of Drp1-mediated mitochondrial fission

Autor: Xiangmei Chen, Yang Wang, Meng-Jie Huang, Ping Li, Ri-bao Wei, Ting-Yu Su
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Ach
Acetylcholine
Clinical Biochemistry
Vasodilation
vWF
von Willebrand factor
030204 cardiovascular system & hematology
medicine.disease_cause
Biochemistry
Mitochondrial Dynamics
GTP Phosphohydrolases
ICAM-1
intercellular cell adhesion molecule-1
0302 clinical medicine
PE
phenylephrine hydrochloride
Enos
ESRD
end-stage renal disease
Chronic kidney disease
Endothelial dysfunction
lcsh:QH301-705.5
Aorta
chemistry.chemical_classification
lcsh:R5-920
biology
Mitochondrial fission
Hippurates
Hippurate
eNOS
endothelial nitric oxide synthase
Intercellular Adhesion Molecule-1
Drp1
Dynamin-related protein 1
SNP
sodium nitroprusside
medicine.symptom
lcsh:Medicine (General)
Microtubule-Associated Proteins
Research Paper
HAECs
human aortic endothelial cells
Dynamins
medicine.medical_specialty
Nitric Oxide Synthase Type III
qRT-PCR
quantitative reverse transcription polymerase chain reaction
Inflammation
CVD
cardiovascular disease
mitoROS
mitochondrial ROS
Mdivi-1
mitochondrial division inhibitor 1
Mitochondrial Proteins
03 medical and health sciences
ROS
reactive oxygen species
Von Willebrand factor
Internal medicine
CCK8
Cell Counting Kit-8
von Willebrand Factor
medicine
Animals
Humans
Renal Insufficiency
Chronic
Fis1
fission 1
Reactive oxygen species
Organic Chemistry
CKD
chronic kidney disease
Endothelial Cells
medicine.disease
biology.organism_classification
Atherosclerosis
Rats
Oxidative Stress
030104 developmental biology
Endocrinology
chemistry
Gene Expression Regulation
lcsh:Biology (General)
siRNA
small interfering RNA
Mff
mitochondrial fission factor
biology.protein
Reactive Oxygen Species
DHE
dihydroethidium
Oxidative stress
Zdroj: Redox Biology, Vol 16, Iss, Pp 303-313 (2018)
Redox Biology
ISSN: 2213-2317
Popis: The accumulation of uremic toxins in chronic kidney disease (CKD) induces inflammation, oxidative stress and endothelial dysfunction, which is a key step in atherosclerosis. Accumulating evidence indicates increased mitochondrial fission is a contributing mechanism for impaired endothelial function. Hippurate, a uremic toxin, has been reported to be involved in cardiovascular diseases. Here, we assessed the endothelial toxicity of hippurate and the contribution of altered mitochondrial dynamics to hippurate-induced endothelial dysfunction. Treatment of human aortic endothelial cells with hippurate reduced the expression of endothelial nitric oxide synthase (eNOS) and increased the expression of intercellular cell adhesion molecule-1 (ICAM-1) and von Willebrand factor (vWF). The mechanisms of hippurate-induced endothelial dysfunction in vitro depended on the activation of Dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and overproduction of mitochondrial reactive oxygen species (mitoROS). In a rat model in which CKD was induced by 5/6 nephrectomy (CKD rat), we observed increased oxidative stress, impaired endothelium-dependent vasodilation, and elevated soluble biomarkers of endothelial dysfunction (ICAM-1 and vWF). Similarly, endothelial dysfunction was identified in healthy rats treated with disease-relevant concentrations of hippurate. In aortas of CKD rats and hippurate-treated rats, we observed an increase in Drp1 protein levels and mitochondrial fission. Inhibition of Drp1 improved endothelial function in both rat models. These results indicate that hippurate, by itself, can cause endothelial dysfunction. Increased mitochondrial fission plays an active role in hippurate-induced endothelial dysfunction via an increase in mitoROS.
Graphical abstract fx1
Highlights • Hippurate causes pro-atherogenic and pro-inflammatory effects on endothelium. • Mitochondrial fission contributes to HA-induced endothelial dysfunction via mitoROS. • Drp1 inhibition protects endothelium from HA-induced endothelial toxicity.
Databáze: OpenAIRE
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