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The uremic toxin hippurate promotes endothelial dysfunction via the activation of
Drp1-mediated mitochondrial fission
#MMPMID29573704
Huang M
; Wei R
; Wang Y
; Su T
; Li P
; Chen X
Redox Biol
2018[Jun]; 16
(?): 303-313
PMID29573704
show ga
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.
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