Oral activated charcoal adsorbent (AST-120) ameliorates extent and instability of atherosclerosis accelerated by kidney disease in apolipoprotein E-deficient mice.
BACKGROUND
Accelerated atherosclerosis and increased cardiovascular events are not only more common in chronic kidney disease (CKD) but are more resistant to therapeutic interventions effective in the general population. The oral charcoal adsorbent, AST-120, currently used to delay start of dialysis, reduces circulating and tissue uremic toxins, which may contribute to vasculopathy, including atherosclerosis. We, therefore, investigated whether AST-120 affects CKD-induced atherosclerosis.


METHODS
Apolipoprotein E-deficient mice, a model of atherosclerosis, underwent uninephrectomy, subtotal nephrectomy or sham operation at 8 weeks of age and were treated with AST-120 after renal ablation. Atherosclerosis and its characteristics were assessed at 25 weeks of age.


RESULTS
Uninephrectomy and subtotal nephrectomised mice had significantly increased acceleration of atherosclerosis. AST-120 treatment dramatically reduced the atherosclerotic burden in mice with kidney damage, while there was no beneficial effect in sham-operated mice. The benefit was independent of blood pressure, serum total cholesterol or creatinine clearance. AST-120 significantly decreased necrotic areas and lessened aortic deposition of the uremic toxin indoxyl sulfate without affecting lesional macrophage or collagen content. Furthermore, AST-120 lessened aortic expression of monocyte chemoattractant protein-1, tumor necrosis factor-α and interleukin-1β messenger RNA.


CONCLUSIONS
AST-120 lessens the extent of atherosclerosis induced by kidney injury and alters lesion characteristics in apolipoprotein E-deficient mice, resulting in plaques with a more stable phenotype with less necrosis and reduced inflammation.
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
Suguru
S
Yamamoto
Yiqin
Y
Zuo
Ji
J
Ma
Patricia G
PG
Yancey
Tracy E
TE
Hunley
Masaru
M
Motojima
Agnes B
AB
Fogo
Macrae F
MF
Linton
Sergio
S
Fazio
Iekuni
I
Ichikawa
Valentina
V
Kon
D000284:Administration, Oral; D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology*; D050197:Atherosclerosis / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D002244:Carbon / Q000008:administration & dosage* / Q000494:pharmacology; D002606:Charcoal / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D007124:Immunoenzyme Techniques; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007674:Kidney Diseases / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010087:Oxides / Q000008:administration & dosage* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D001057:Apolipoproteins E; D018932:Chemokine CCL2; D053583:Interleukin-1beta; D010087:Oxides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D002606:Charcoal; D002244:Carbon; C040896:AST 120
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