Abstract
Soluble Flt-1 (sFlt-1), an endogenous antagonist of the proatherogenic cytokine placental growth factor, is decreased in chronic kidney disease (CKD), leading to atherosclerotic progression. In this study, we investigated the effect of AST-120, an oral carbon adsorbent which can remove uremic toxins, on sFlt-1 expression levels and atherosclerosis progression. Atherosclerotic apolipoprotein E-deficient mice underwent a 5/6 nephrectomy (5/6 NR) or a sham operation (sham) at 8 weeks of age and were then treated or not with oral AST-120 for 12 weeks. sFlt-1 expression levels and the degree of atherosclerosis were assessed at 22 weeks of age in each of the four groups (sham; n = 7, 5/6 NR; n = 10, sham + AST-120: n = 8, 5/6 NR + AST-120; n = 8). The expression levels of sFlt-1 mRNA in the kidney were significantly lower in the 5/6 NR group than in the sham group, but AST-120 treatment prevented this decrease in sFlt-1 levels. Similarly, the atherosclerotic plaque area of the thoracoabdominal aorta was significantly larger in the 5/6 NR group than in the sham group, and AST-120 treatment prevented this increase in atherosclerosis. AST-120 could, therefore, be used as a therapeutic to treat atherosclerosis in patients with CKD.
Highlights
Cardiac events and mortality in patients with CKD19
This study suggests the possibility that uremic toxins present in patients with chronic kidney disease (CKD) lead to a decrease in Soluble Flt-1 (sFlt-1) expression and that AST-120 can suppress the progression of atherosclerosis by removal of these uremic toxins
The pathophysiology of atherosclerosis in patients with CKD arises not from a single factor but from multiple factors, and it is thought that both risk factors that induce CKD such as diabetes or hypertension and mechanisms that are further exacerbated in CKD, such as chronic inflammation derived from activation of the PlGF/Flt-1 pathway, vascular endothelial damage due to the renin-angiotensin system, or sympathetic nerve stimulation and the dysregulation of calcium and phosphorus, are involved[20,21]
Summary
Cardiac events and mortality in patients with CKD19. Since no drugs have been developed to regulate the production of sFlt-1 so far, in this study, we investigated the effect of AST-120 on sFlt-1 expression levels and the impact on atherosclerotic progression. To investigate the mechanisms underlying the reduction in sFlt-1 expression in patients with CKD, cultured human umbilical artery endothelial cells (HUAECs) were incubated with uremic toxins. The expression levels of sFlt-1 mRNA were significantly decreased in cultures with uremic toxins compared with those in control cultures (n = 4, p < 0.05).
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