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The Soluble Fms-like Tyrosine Kinase-1 Contributes to Structural and Functional Changes in Endothelial Cells in Chronic Kidney Disease

Endothelial cells are a critical target of the soluble Fms-like tyrosine kinase-1 (sFlt-1), a soluble factor increased in different diseases with varying degrees of renal impairment and endothelial dysfunction, including chronic kidney disease (CKD). Although the mechanisms underlying endothelial dysfunction are multifactorial and complex, herein, we investigated the damaging effects of sFlt-1 on structural and functional changes in endothelial cells. Our results evidenced that sera from patients with CKD stiffen the endothelial cell cortex in vitro, an effect correlated with sFlt-1 levels and prevented by sFlt-1 neutralization. Besides, we could show that recombinant sFlt-1 leads to endothelial stiffening in vitro and in vivo. This was accompanied by cytoskeleton reorganization and changes in the endothelial barrier function, as observed by increased actin polymerization and endothelial cell permeability, respectively. These results depended on the activation of the p38 MAPK and were blocked by the specific inhibitor SB203580. However, sFlt-1 only minimally affected the expression of stiffness-sensitive genes. These findings bring new insight into the mechanism of action of sFlt-1 and its biological effects that cannot be exclusively ascribed to the regulation of angiogenesis.

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S1076 Adezmapimod (SB203580) Adezmapimod (SB203580, RWJ 64809, PB 203580) is a p38 MAPK inhibitor with IC50 of 0.3-0.5 μM in THP-1 cells, 10-fold less sensitive to SAPK3(106T) and SAPK4(106T) and blocks PKB phosphorylation with IC50 of 3-5 μM. SB203580 induces mitophagy and autophagy.

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p38 MAPK Mitophagy