The Soluble VEGF Receptor sFlt1 Contributes to Endothelial Dysfunction in CKD

Abstract

Endothelial dysfunction contributes to the increased cardiovascular risk that accompanies CKD. We hypothesized that the soluble VEGF receptor 1 (sFlt-1), a VEGF antagonist, plays a role in endothelial dysfunction and decreased angiogenesis in CKD. We enrolled 130 patients with CKD stages 3 to 5 and 56 age-and gender-matched control patients. Plasma sFlt-1 levels were higher in patients with CKD and, after multivariate regression analyses, exclusively associated with renal function and levels of vWF, a marker of endothelial dysfunction. Compared with serum from control patients, both recombinant sFlt-1 and serum from patients with CKD had antiangiogenic activity in the chick chorioallantoic membrane (CAM) assay, induced endothelial cell apoptosis in vitro, and decreased nitric oxide generation in two different endothelial cell lines. Pretreating the sera with an antibody against sFlt-1 abrogated all of these effects. Furthermore, we observed increased sFlt1 levels in 5/6-nephrectomized rats compared with sham-operated animals. Finally, using real-time PCR and ELISA, we identified monocytes as a possible source of increased sFlt-1 in patients with CKD. Our findings show that excess sFlt-1 associates with endothelial dysfunction in CKD and suggest that increased sFlt-1 may predict cardiovascular risk in CKD.

Hydrogen Sulfide Attenuates sFlt1-Induced Hypertension and Renal Damage by Upregulating Vascular Endothelial Growth Factor

“…3,5,6,35,36 H 2 S is known for its proangiogenic, antihypertensive, and organ protective properties. 28,37,38 In this study, we investigated the effects of exogenously administrated H 2 S in a rat model for severe endothelial dysfunction, induced by overexpression of sFlt1.…”

“…[1][2][3] In preeclampsia, a consistent line of evidence has shown that increased sFlt1 is one of the major contributors to the development of hypertension and proteinuria. [4][5][6][7] sFlt1 is a splice variant of the vascular endothelial growth factor (VEGF) receptor lacking the transmembrane and cytoplasmic domains and acts as a powerful antagonist of VEGF, thereby inhibiting VEGF signaling in the vasculature.…”

Soluble Fms-like Tyrosine Kinase 1 Is a Novel Predictor of Brain Natriuretic Peptide Elevation

“…In a previous study, Di Marco, et al also reported that sFlt-1 levels were independently associated with renal dysfunction. 29) In experimental animal models, exogenous administration of sFlt-1 to either pregnant or nonpregnant animals was found to induce widespread endothelial dysfunction, hypertension, and renal dysfunction. 10,30) These data suggest that the antiangiogenic effects of sFlt-1 may affect compensatory angiogenesis in diseased kidneys and failing hearts.…”

Endothelial dysfunction and hypertension in obstructive sleep apnea – Is it due to intermittent hypoxia?

“…17 These angiogenesis inhibitors are released under inflammatory state. 18,19 These circulating proteins have been shown to have pathogenetic roles in hypertension in preeclampsia, 20 in human chronic kidney disease, 21 coronary artery disease 22 and in animal models of hypertension. 23,24 However, none of the studies have examined the relationship between endothelial dysfunction and hypertension in relationship to hypoxia exposure in OSA patients.…”