Selective Targeting of Vascular Endothelial YAP Activity Blocks EndMT and Ameliorates Unilateral Ureteral Obstruction-Induced Kidney Fibrosis

Kidney fibrosis is accompanied by
vascular dysfunction. Discovering
new ways to ameliorate dysfunctional angiogenesis may bypass kidney
fibrosis. YAP (Yes-associated protein) plays a multifaceted role during
angiogenesis. Here, we found that selectively targeting YAP signaling
in the endothelium ameliorates unilateral ureteral obstruction (UUO)-induced
kidney fibrosis. Genetic deletion of Yap1, encoding
YAP protein, in VE-cadherin+ endothelial cells inhibited
endothelial-to-mesenchymal transition (EndMT) and dysfunctional angiogenesis
and improved obstructive nephropathy and kidney fibrosis. Treatment
with the systemic YAP inhibitor verteporfin worsened kidney fibrosis
symptoms because of its lack of cell specificity. In an attempt to
identify endothelial-specific YAP modulators, we found that G-protein-coupled
receptor coagulation factor II receptor-like 1 (F2RL1) was highly
expressed in vessels after UUO-induced kidney fibrosis. The F2RL1
peptide antagonist FSLLRY-NH2 selectively blocked YAP activity in
endothelial cells and ameliorated kidney fibrosis. Thus, selective
antagonization of endothelial YAP activity might bypass kidney fibrosis
and provide new avenues for the design of antifibrotic therapies.